GYRA_ECOLI
ID GYRA_ECOLI Reviewed; 875 AA.
AC P0AES4; P09097;
DT 20-DEC-2005, integrated into UniProtKB/Swiss-Prot.
DT 20-DEC-2005, sequence version 1.
DT 03-AUG-2022, entry version 154.
DE RecName: Full=DNA gyrase subunit A {ECO:0000255|HAMAP-Rule:MF_01897};
DE EC=5.6.2.2 {ECO:0000255|HAMAP-Rule:MF_01897, ECO:0000269|PubMed:12051842, ECO:0000269|PubMed:18642932, ECO:0000269|PubMed:186775, ECO:0000269|PubMed:19965760, ECO:0000269|PubMed:9278055};
GN Name=gyrA {ECO:0000255|HAMAP-Rule:MF_01897};
GN Synonyms=hisW, nalA {ECO:0000303|PubMed:337300}, parD;
GN OrderedLocusNames=b2231, JW2225;
OS Escherichia coli (strain K12).
OC Bacteria; Proteobacteria; Gammaproteobacteria; Enterobacterales;
OC Enterobacteriaceae; Escherichia.
OX NCBI_TaxID=83333;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2828631; DOI=10.1016/0022-2836(87)90479-7;
RA Swanberg S.L., Wang J.C.;
RT "Cloning and sequencing of the Escherichia coli gyrA gene coding for the A
RT subunit of DNA gyrase.";
RL J. Mol. Biol. 197:729-736(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=K12 / KL16;
RX PubMed=2830458; DOI=10.1007/bf00338386;
RA Yoshida H., Kojima T., Yamagishi J., Nakamura S.;
RT "Quinolone-resistant mutations of the gyrA gene of Escherichia coli.";
RL Mol. Gen. Genet. 211:1-7(1988).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS QUINOLONE-RESISTANTS ASN-87
RP AND ILE-MET-MET-ILE-798.
RC STRAIN=OV6;
RX PubMed=2834621; DOI=10.1111/j.1365-2958.1987.tb01932.x;
RA Hussain K., Elliott E.J., Salmond G.P.C.;
RT "The parD- mutant of Escherichia coli also carries a gyrAam mutation. The
RT complete sequence of gyrA.";
RL Mol. Microbiol. 1:259-273(1987).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS QUINOLONE-RESISTANT GLU-678
RP AND SER-828.
RC STRAIN=227;
RX PubMed=2548439; DOI=10.1128/aac.33.6.886;
RA Cullen M.E., Wyke A.W., Kuroda R., Fisher L.M.;
RT "Cloning and characterization of a DNA gyrase A gene from Escherichia coli
RT that confers clinical resistance to 4-quinolones.";
RL Antimicrob. Agents Chemother. 33:886-894(1989).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=K12 / W3110 / ATCC 27325 / DSM 5911;
RX PubMed=9205837; DOI=10.1093/dnares/4.2.91;
RA Yamamoto Y., Aiba H., Baba T., Hayashi K., Inada T., Isono K., Itoh T.,
RA Kimura S., Kitagawa M., Makino K., Miki T., Mitsuhashi N., Mizobuchi K.,
RA Mori H., Nakade S., Nakamura Y., Nashimoto H., Oshima T., Oyama S.,
RA Saito N., Sampei G., Satoh Y., Sivasundaram S., Tagami H., Takahashi H.,
RA Takeda J., Takemoto K., Uehara K., Wada C., Yamagata S., Horiuchi T.;
RT "Construction of a contiguous 874-kb sequence of the Escherichia coli-K12
RT genome corresponding to 50.0-68.8 min on the linkage map and analysis of
RT its sequence features.";
RL DNA Res. 4:91-113(1997).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=K12 / MG1655 / ATCC 47076;
RX PubMed=9278503; DOI=10.1126/science.277.5331.1453;
RA Blattner F.R., Plunkett G. III, Bloch C.A., Perna N.T., Burland V.,
RA Riley M., Collado-Vides J., Glasner J.D., Rode C.K., Mayhew G.F.,
RA Gregor J., Davis N.W., Kirkpatrick H.A., Goeden M.A., Rose D.J., Mau B.,
RA Shao Y.;
RT "The complete genome sequence of Escherichia coli K-12.";
RL Science 277:1453-1462(1997).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=K12 / W3110 / ATCC 27325 / DSM 5911;
RX PubMed=16738553; DOI=10.1038/msb4100049;
RA Hayashi K., Morooka N., Yamamoto Y., Fujita K., Isono K., Choi S.,
RA Ohtsubo E., Baba T., Wanner B.L., Mori H., Horiuchi T.;
RT "Highly accurate genome sequences of Escherichia coli K-12 strains MG1655
RT and W3110.";
RL Mol. Syst. Biol. 2:E1-E5(2006).
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-88, AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=3029031; DOI=10.1128/jb.169.3.1272-1278.1987;
RA Menzel R., Gellert M.;
RT "Fusions of the Escherichia coli gyrA and gyrB control regions to the
RT galactokinase gene are inducible by coumermycin treatment.";
RL J. Bacteriol. 169:1272-1278(1987).
RN [9]
RP PROTEIN SEQUENCE OF 17-24; 61-66 AND 123-126, FUNCTION, ACTIVE SITE,
RP REACTION MECHANISM, AND DNA-BINDING.
RX PubMed=3031051; DOI=10.1016/s0021-9258(18)61193-7;
RA Horowitz D.S., Wang J.C.;
RT "Mapping the active site tyrosine of Escherichia coli DNA gyrase.";
RL J. Biol. Chem. 262:5339-5344(1987).
RN [10]
RP FUNCTION IN GENERATING NEGATIVELY SUPERCOILED DNA, CATALYTIC ACTIVITY, AND
RP ATP-DEPENDENCE.
RX PubMed=186775; DOI=10.1073/pnas.73.11.3872;
RA Gellert M., Mizuuchi K., O'Dea M.H., Nash H.A.;
RT "DNA gyrase: an enzyme that introduces superhelical turns into DNA.";
RL Proc. Natl. Acad. Sci. U.S.A. 73:3872-3876(1976).
RN [11]
RP FUNCTION IN RELAXING SUPERCOILED DNA, AND ACTIVITY REGULATION.
RX PubMed=337300; DOI=10.1073/pnas.74.11.4772;
RA Gellert M., Mizuuchi K., O'Dea M.H., Itoh T., Tomizawa J.I.;
RT "Nalidixic acid resistance: a second genetic character involved in DNA
RT gyrase activity.";
RL Proc. Natl. Acad. Sci. U.S.A. 74:4772-4776(1977).
RN [12]
RP VARIANTS QUINOLONE-RESISTANT SER-67; CYS-81; LEU-83; TRP-83; PRO-84; ASN-87
RP AND HIS-106.
RC STRAIN=K12 / KL16;
RX PubMed=2168148; DOI=10.1128/aac.34.6.1271;
RA Yoshida H., Bogaki M., Nakamura M., Nakamura S.;
RT "Quinolone resistance-determining region in the DNA gyrase gyrA gene of
RT Escherichia coli.";
RL Antimicrob. Agents Chemother. 34:1271-1272(1990).
RN [13]
RP VARIANTS QUINOLONE-RESISTANT LEU-83; TRP-83 AND VAL-87.
RX PubMed=1850972; DOI=10.1128/aac.35.2.387;
RA Oram M., Fisher L.M.;
RT "4-quinolone resistance mutations in the DNA gyrase of Escherichia coli
RT clinical isolates identified by using the polymerase chain reaction.";
RL Antimicrob. Agents Chemother. 35:387-389(1991).
RN [14]
RP MUTAGENESIS OF SER-83 AND GLN-106.
RC STRAIN=K12;
RX PubMed=1850970; DOI=10.1128/aac.35.2.335;
RA Hallett P., Maxwell A.;
RT "Novel quinolone resistance mutations of the Escherichia coli DNA gyrase A
RT protein: enzymatic analysis of the mutant proteins.";
RL Antimicrob. Agents Chemother. 35:335-340(1991).
RN [15]
RP INHIBITION BY TOXIN PROTEIN CCDB, AND MUTAGENESIS OF ARG-462.
RC STRAIN=K12;
RX PubMed=1324324; DOI=10.1016/0022-2836(92)90629-x;
RA Bernard P., Couturier M.;
RT "Cell killing by the F plasmid CcdB protein involves poisoning of DNA-
RT topoisomerase II complexes.";
RL J. Mol. Biol. 226:735-745(1992).
RN [16]
RP MUTAGENESIS OF ARG-462.
RX PubMed=8254658; DOI=10.1006/jmbi.1993.1609;
RA Bernard P., Kezdy K.E., Van Melderen L., Steyaert J., Wyns L., Pato M.L.,
RA Higgins P.N., Couturier M.;
RT "The F plasmid CcdB protein induces efficient ATP-dependent DNA cleavage by
RT gyrase.";
RL J. Mol. Biol. 234:534-541(1993).
RN [17]
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=7811004; DOI=10.1128/aac.38.9.1966;
RA Nakada N., Gmuender H., Hirata T., Arisawa M.;
RT "Mechanism of inhibition of DNA gyrase by cyclothialidine, a novel DNA
RT gyrase inhibitor.";
RL Antimicrob. Agents Chemother. 38:1966-1973(1994).
RN [18]
RP INHIBITION BY TOXIN PROTEIN CCDB, REJUVENATION BY CCDA, AND SUBUNIT.
RX PubMed=8604132; DOI=10.1006/jmbi.1996.0102;
RA Maki S., Takiguchi S., Horiuchi T., Sekimizu K., Miki T.;
RT "Partner switching mechanisms in inactivation and rejuvenation of
RT Escherichia coli DNA gyrase by F plasmid proteins LetD (CcdB) and LetA
RT (CcdA).";
RL J. Mol. Biol. 256:473-482(1996).
RN [19]
RP FUNCTION, AND DOMAIN.
RX PubMed=8962066; DOI=10.1073/pnas.93.25.14416;
RA Kampranis S.C., Maxwell A.;
RT "Conversion of DNA gyrase into a conventional type II topoisomerase.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:14416-14421(1996).
RN [20]
RP FUNCTION, ACTIVITY REGULATION, SUBUNIT, AND DNA-BINDING.
RC STRAIN=K12 / N2879;
RX PubMed=9148951; DOI=10.1074/jbc.272.20.13302;
RA Funatsuki K., Tanaka R., Inagaki S., Konno H., Katoh K., Nakamura H.;
RT "acrB mutation located at carboxyl-terminal region of gyrase B subunit
RT reduces DNA binding of DNA gyrase.";
RL J. Biol. Chem. 272:13302-13308(1997).
RN [21]
RP IDENTIFICATION BY 2D-GEL.
RX PubMed=9298644; DOI=10.1002/elps.1150180805;
RA VanBogelen R.A., Abshire K.Z., Moldover B., Olson E.R., Neidhardt F.C.;
RT "Escherichia coli proteome analysis using the gene-protein database.";
RL Electrophoresis 18:1243-1251(1997).
RN [22]
RP FUNCTION.
RX PubMed=9334322; DOI=10.1101/gad.11.19.2580;
RA Zechiedrich E.L., Khodursky A.B., Cozzarelli N.R.;
RT "Topoisomerase IV, not gyrase, decatenates products of site-specific
RT recombination in Escherichia coli.";
RL Genes Dev. 11:2580-2592(1997).
RN [23]
RP IDENTIFICATION AND DISCUSSION OF GYRA-BOX, AND DOMAIN.
RX PubMed=9426128; DOI=10.1046/j.1365-2958.1997.6242005.x;
RA Ward D.V., Newton A.;
RT "Requirement of topoisomerase IV parC and parE genes for cell cycle
RT progression and developmental regulation in Caulobacter crescentus.";
RL Mol. Microbiol. 26:897-910(1997).
RN [24]
RP FUNCTION, CATALYTIC ACTIVITY, SUBUNIT, AND MUTAGENESIS OF ARG-32; ARG-47;
RP HIS-78 AND HIS-80.
RX PubMed=12051842; DOI=10.1016/s0022-2836(02)00048-7;
RA Hockings S.C., Maxwell A.;
RT "Identification of four GyrA residues involved in the DNA breakage-reunion
RT reaction of DNA gyrase.";
RL J. Mol. Biol. 318:351-359(2002).
RN [25]
RP FUNCTION, AND MUTAGENESIS OF 560-GLN--GLY-566.
RX PubMed=16332690; DOI=10.1074/jbc.m511160200;
RA Kramlinger V.M., Hiasa H.;
RT "The 'GyrA-box' is required for the ability of DNA gyrase to wrap DNA and
RT catalyze the supercoiling reaction.";
RL J. Biol. Chem. 281:3738-3742(2006).
RN [26]
RP FUNCTION.
RC STRAIN=K12 / W3110 / ATCC 27325 / DSM 5911;
RX PubMed=17400739; DOI=10.1128/jb.00083-07;
RA Champion K., Higgins N.P.;
RT "Growth rate toxicity phenotypes and homeostatic supercoil control
RT differentiate Escherichia coli from Salmonella enterica serovar
RT Typhimurium.";
RL J. Bacteriol. 189:5839-5849(2007).
RN [27]
RP FUNCTION, CATALYTIC ACTIVITY, AND SUBUNIT.
RX PubMed=18642932; DOI=10.1021/bi800480j;
RA Sissi C., Chemello A., Vazquez E., Mitchenall L.A., Maxwell A., Palumbo M.;
RT "DNA gyrase requires DNA for effective two-site coordination of divalent
RT metal ions: further insight into the mechanism of enzyme action.";
RL Biochemistry 47:8538-8545(2008).
RN [28]
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=19060136; DOI=10.1128/jb.01205-08;
RA Merens A., Matrat S., Aubry A., Lascols C., Jarlier V., Soussy C.J.,
RA Cavallo J.D., Cambau E.;
RT "The pentapeptide repeat proteins MfpAMt and QnrB4 exhibit opposite effects
RT on DNA gyrase catalytic reactions and on the ternary gyrase-DNA-quinolone
RT complex.";
RL J. Bacteriol. 191:1587-1594(2009).
RN [29]
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=20356737; DOI=10.1016/j.bmcl.2010.03.052;
RA Ronkin S.M., Badia M., Bellon S., Grillot A.L., Gross C.H., Grossman T.H.,
RA Mani N., Parsons J.D., Stamos D., Trudeau M., Wei Y., Charifson P.S.;
RT "Discovery of pyrazolthiazoles as novel and potent inhibitors of bacterial
RT gyrase.";
RL Bioorg. Med. Chem. Lett. 20:2828-2831(2010).
RN [30]
RP FUNCTION, DOMAIN, DNA-BINDING, AND MUTAGENESIS OF 842-PRO--ALA-856 AND
RP 854-SER--GLU-875.
RX PubMed=22457353; DOI=10.1074/jbc.m112.345678;
RA Tretter E.M., Berger J.M.;
RT "Mechanisms for defining supercoiling set point of DNA gyrase orthologs: I.
RT A nonconserved acidic C-terminal tail modulates Escherichia coli gyrase
RT activity.";
RL J. Biol. Chem. 287:18636-18644(2012).
RN [31]
RP FUNCTION, DNA-BINDING, AND MUTAGENESIS OF 842-PRO--ALA-856.
RX PubMed=22457352; DOI=10.1074/jbc.m112.345736;
RA Tretter E.M., Berger J.M.;
RT "Mechanisms for defining supercoiling set point of DNA gyrase orthologs:
RT II. The shape of the GyrA subunit C-terminal domain (CTD) is not a sole
RT determinant for controlling supercoiling efficiency.";
RL J. Biol. Chem. 287:18645-18654(2012).
RN [32]
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=23294697; DOI=10.1016/j.bmcl.2012.11.073;
RA Trzoss M., Bensen D.C., Li X., Chen Z., Lam T., Zhang J., Creighton C.J.,
RA Cunningham M.L., Kwan B., Stidham M., Nelson K., Brown-Driver V.,
RA Castellano A., Shaw K.J., Lightstone F.C., Wong S.E., Nguyen T.B., Finn J.,
RA Tari L.W.;
RT "Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV
RT (ParE), Part II: development of inhibitors with broad spectrum, Gram-
RT negative antibacterial activity.";
RL Bioorg. Med. Chem. Lett. 23:1537-1543(2013).
RN [33]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 30-522, AND CATALYTIC ACTIVITY.
RX PubMed=9278055; DOI=10.1038/42294;
RA Morais Cabral J.H., Jackson A.P., Smith C.V., Shikotra N., Maxwell A.,
RA Liddington R.C.;
RT "Crystal structure of the breakage-reunion domain of DNA gyrase.";
RL Nature 388:903-906(1997).
RN [34]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 363-494 IN COMPLEX WITH CCBD, AND
RP SUBUNIT.
RX PubMed=15854646; DOI=10.1016/j.jmb.2005.03.049;
RA Dao-Thi M.H., Van Melderen L., De Genst E., Afif H., Buts L., Wyns L.,
RA Loris R.;
RT "Molecular basis of gyrase poisoning by the addiction toxin CcdB.";
RL J. Mol. Biol. 348:1091-1102(2005).
RN [35]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 535-841, AND DOMAIN.
RC STRAIN=K12;
RX PubMed=15897198; DOI=10.1074/jbc.m502838200;
RA Ruthenburg A.J., Graybosch D.M., Huetsch J.C., Verdine G.L.;
RT "A superhelical spiral in the Escherichia coli DNA gyrase A C-terminal
RT domain imparts unidirectional supercoiling bias.";
RL J. Biol. Chem. 280:26177-26184(2005).
RN [36]
RP X-RAY CRYSTALLOGRAPHY (2.62 ANGSTROMS) OF 1-525 IN COMPLEX WITH ANTIBIOTIC,
RP FUNCTION, CATALYTIC ACTIVITY, AND SUBUNIT.
RX PubMed=19965760; DOI=10.1126/science.1179123;
RA Edwards M.J., Flatman R.H., Mitchenall L.A., Stevenson C.E., Le T.B.,
RA Clarke T.A., McKay A.R., Fiedler H.P., Buttner M.J., Lawson D.M.,
RA Maxwell A.;
RT "A crystal structure of the bifunctional antibiotic simocyclinone D8, bound
RT to DNA gyrase.";
RL Science 326:1415-1418(2009).
CC -!- FUNCTION: A type II topoisomerase that negatively supercoils closed
CC circular double-stranded (ds) DNA in an ATP-dependent manner to
CC maintain chromosomes in an underwound state (PubMed:3031051,
CC PubMed:186775, PubMed:7811004, PubMed:9148951, PubMed:12051842,
CC PubMed:18642932, PubMed:19060136, PubMed:20356737, PubMed:22457353,
CC PubMed:23294697, PubMed:19965760). This makes better substrates for
CC topoisomerase IV (ParC and ParE) which is the main enzyme that unlinks
CC newly replicated chromosomes in E.coli (PubMed:9334322). Gyrase
CC catalyzes the interconversion of other topological isomers of dsDNA
CC rings, including catenanes (PubMed:22457352). Relaxes negatively
CC supercoiled DNA in an ATP-independent manner (PubMed:337300). E.coli
CC gyrase has higher supercoiling activity than many other bacterial
CC gyrases; at comparable concentrations E.coli gyrase introduces more
CC supercoils faster than M.tuberculosis gyrase, while M.tuberculosis
CC gyrase has higher decatenation than supercoiling activity compared to
CC E.coli (PubMed:22457352). E.coli makes 15% more negative supercoils in
CC pBR322 plasmid DNA than S.typhimurium; the S.typhimurium GyrB subunit
CC is toxic in E.coli, while the E.coli copy can be expressed in
CC S.typhimurium even though the 2 subunits have 777/804 residues
CC identical (PubMed:17400739). The enzymatic differences between E.coli
CC gyrase and topoisomerase IV are largely due to the GyrA C-terminal
CC domain (approximately residues 524-841) and specifically the GyrA-box
CC (PubMed:8962066, PubMed:16332690). {ECO:0000269|PubMed:12051842,
CC ECO:0000269|PubMed:16332690, ECO:0000269|PubMed:17400739,
CC ECO:0000269|PubMed:18642932, ECO:0000269|PubMed:186775,
CC ECO:0000269|PubMed:19060136, ECO:0000269|PubMed:19965760,
CC ECO:0000269|PubMed:20356737, ECO:0000269|PubMed:22457352,
CC ECO:0000269|PubMed:22457353, ECO:0000269|PubMed:23294697,
CC ECO:0000269|PubMed:3031051, ECO:0000269|PubMed:337300,
CC ECO:0000269|PubMed:7811004, ECO:0000269|PubMed:8962066,
CC ECO:0000269|PubMed:9148951, ECO:0000269|PubMed:9334322}.
CC -!- FUNCTION: Negative supercoiling favors strand separation, and DNA
CC replication, transcription, recombination and repair, all of which
CC involve strand separation. Type II topoisomerases break and join 2 DNA
CC strands simultaneously in an ATP-dependent manner.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP-dependent breakage, passage and rejoining of double-
CC stranded DNA.; EC=5.6.2.2; Evidence={ECO:0000255|HAMAP-Rule:MF_01897,
CC ECO:0000269|PubMed:12051842, ECO:0000269|PubMed:18642932,
CC ECO:0000269|PubMed:186775, ECO:0000269|PubMed:19965760,
CC ECO:0000269|PubMed:9278055};
CC -!- ACTIVITY REGULATION: Gyrase is the target of many classes of
CC inhibitors, including coumarins, cyclothialidines, pyrrolopyrimidines,
CC pyrazolthiazoles and (fluoro)quinolones. Quinolones bind GyrA when the
CC enzyme is complexed with DNA and trap the enzyme in a covalent reaction
CC intermediate with DNA (PubMed:3031051, PubMed:12051842). Coumarins bind
CC to GyrB and are competitive inhibitors of its ATPase activity
CC (PubMed:7811004). Cyclothialidines also bind GyrB and are ATPase
CC competitive inhibitors; they seem to act differently from coumarins
CC (PubMed:7811004). Pyrrolopyrimidines inhibit both GyrB and its paralog
CC in topoisomerase IV (parE) (PubMed:23294697). Pyrazolthiazoles also
CC inhibit the ATPase activity of GyrB (PubMed:20356737). DNA supercoiling
CC and relaxation are both inhibited by oxolinic acid (PubMed:337300).
CC Acriflavine inhibits supercoiling activity and DNA-stimulated ATPase
CC activity (PubMed:9148951). DNA supercoiling activity is protected from
CC fluoroquinolone inhibition by QnrB4; QnrB4 has no effect on
CC supercoiling activity alone (PubMed:19060136).
CC {ECO:0000269|PubMed:19060136, ECO:0000269|PubMed:20356737,
CC ECO:0000269|PubMed:23294697, ECO:0000269|PubMed:337300,
CC ECO:0000269|PubMed:7811004, ECO:0000269|PubMed:9148951}.
CC -!- SUBUNIT: Heterotetramer, composed of two GyrA and two GyrB chains
CC (PubMed:9148951, PubMed:12051842). In the heterotetramer, GyrA contains
CC the active site tyrosine that forms a transient covalent intermediate
CC with the DNA, while GyrB binds cofactors and catalyzes ATP hydrolysis
CC (PubMed:12051842, PubMed:18642932, PubMed:19965760, PubMed:9148951).
CC Can form a 2:2 complex with toxin CcdB in which GyrA is inactive;
CC rejuvenation of GyrA(2)CcdB(2) is effected by CcdA (PubMed:15854646,
CC PubMed:1324324, PubMed:8254658, PubMed:8604132).
CC {ECO:0000269|PubMed:12051842, ECO:0000269|PubMed:1324324,
CC ECO:0000269|PubMed:15854646, ECO:0000269|PubMed:18642932,
CC ECO:0000269|PubMed:19965760, ECO:0000269|PubMed:8254658,
CC ECO:0000269|PubMed:8604132, ECO:0000269|PubMed:9148951}.
CC -!- INTERACTION:
CC P0AES4; P62554: ccdB; NbExp=3; IntAct=EBI-547129, EBI-25647730;
CC P0AES4; P0AES4: gyrA; NbExp=6; IntAct=EBI-547129, EBI-547129;
CC P0AES4; P0AES6: gyrB; NbExp=7; IntAct=EBI-547129, EBI-541911;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000255|HAMAP-Rule:MF_01897}.
CC -!- DOMAIN: An N-terminal fragment (residues 1-523) can be reconstituted
CC with GyrB, but the complex no longer has negative supercoiling or ATP-
CC independent DNA relaxation activities, although it is capable of DNA
CC cleavage; ATP-dependent relaxation is inhibited by novobiocin and non-
CC hydrolyzable ATP analogs (PubMed:8962066). The fragment has ATP-
CC dependent DNA relaxation and 30-fold improved decatenation activities,
CC unlike holoenzyme it preferentially binds supercoiled DNA
CC (PubMed:8962066). This N-terminal fragment becomes a topoisomerase IV-
CC like enzyme; it poorly complements a temperature-sensitive parC
CC mutation (parC is the topoisomerase IV paralog of gyrA)
CC (PubMed:8962066). {ECO:0000269|PubMed:8962066}.
CC -!- DOMAIN: The C-terminal domain (CTD, approximately residues 535-841)
CC contains 6 tandemly repeated subdomains known as blades, each of which
CC is composed of a 4-stranded antiparallel beta-sheet (PubMed:15897198).
CC The blades form a circular-shaped beta-pinwheel fold arranged in a
CC spiral around a screw axis, to which DNA probably binds, inducing
CC strong positive superhelicity (about 0.8 links/protein)
CC (PubMed:15897198). The non-conserved, C-terminal acidic tail (residues
CC 842-875) regulates wrapping and DNA-binding by the CTD; deletions
CC within the tail show it is autoinhibitory for DNA wrapping and binding,
CC and couples ATP hydrolysis to DNA strand passage (PubMed:22457353). The
CC GyrA-box is a 7 amino acid motif found in the first blade of the CTD
CC which is discriminative for gyrase versus topoisomerase IV activity
CC (PubMed:9426128). The GyrA-box is required for wrapping of DNA around
CC gyrase, and thus is essential for the DNA supercoiling activity but not
CC DNA relaxation or decatenation activities of gyrase (PubMed:16332690).
CC {ECO:0000269|PubMed:15897198, ECO:0000269|PubMed:16332690,
CC ECO:0000269|PubMed:22457353, ECO:0000305|PubMed:9426128}.
CC -!- MISCELLANEOUS: When the enzyme transiently cleaves DNA a
CC phosphotyrosine bond is formed between GyrA and DNA (PubMed:3031051).
CC In the presence of quinolones this intermediate can be trapped and is
CC used as an indicator of drug toxicity (PubMed:12051842). The enzyme-DNA
CC intermediate is also the target of a number of topoisomerase poisons,
CC including toxin CcdB (PubMed:1324324, PubMed:8254658).
CC {ECO:0000269|PubMed:1324324, ECO:0000269|PubMed:3031051,
CC ECO:0000269|PubMed:8254658, ECO:0000305|PubMed:12051842}.
CC -!- MISCELLANEOUS: Few gyrases are as efficient as E.coli at forming
CC negative supercoils (PubMed:22457352, PubMed:17400739). Not all
CC organisms have 2 type II topoisomerases; in organisms with a single
CC type II topoisomerase this enzyme also has to decatenate newly
CC replicated chromosomes. {ECO:0000255|HAMAP-Rule:MF_01897,
CC ECO:0000269|PubMed:17400739, ECO:0000269|PubMed:22457352}.
CC -!- SIMILARITY: Belongs to the type II topoisomerase GyrA/ParC subunit
CC family. {ECO:0000255|HAMAP-Rule:MF_01897}.
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DR EMBL; X06373; CAA29676.1; -; Genomic_DNA.
DR EMBL; X06744; CAA29919.1; -; Genomic_DNA.
DR EMBL; M15631; AAA23948.1; -; Genomic_DNA.
DR EMBL; U00096; AAC75291.1; -; Genomic_DNA.
DR EMBL; AP009048; BAA16048.1; -; Genomic_DNA.
DR EMBL; Y00544; CAA68611.1; -; Genomic_DNA.
DR PIR; S02340; ITECAP.
DR RefSeq; NP_416734.1; NC_000913.3.
DR RefSeq; WP_001281242.1; NZ_LN832404.1.
DR PDB; 1AB4; X-ray; 2.80 A; A=30-522.
DR PDB; 1X75; X-ray; 2.80 A; A/B=363-494.
DR PDB; 1ZI0; X-ray; 2.60 A; A/B=535-841.
DR PDB; 2Y3P; X-ray; 2.62 A; A/B=2-523.
DR PDB; 3NUH; X-ray; 3.10 A; A=1-525.
DR PDB; 4ELY; X-ray; 1.93 A; A/B=363-497.
DR PDB; 6RKS; EM; 4.00 A; A/C=1-875.
DR PDB; 6RKU; EM; 4.00 A; A/C=1-875.
DR PDB; 6RKV; EM; 4.60 A; A/C=1-875.
DR PDB; 6RKW; EM; 6.60 A; A/C=1-875.
DR PDBsum; 1AB4; -.
DR PDBsum; 1X75; -.
DR PDBsum; 1ZI0; -.
DR PDBsum; 2Y3P; -.
DR PDBsum; 3NUH; -.
DR PDBsum; 4ELY; -.
DR PDBsum; 6RKS; -.
DR PDBsum; 6RKU; -.
DR PDBsum; 6RKV; -.
DR PDBsum; 6RKW; -.
DR AlphaFoldDB; P0AES4; -.
DR SMR; P0AES4; -.
DR BioGRID; 4262132; 294.
DR ComplexPortal; CPX-2177; GyrA-GyrB DNA Gyrase complex.
DR ComplexPortal; CPX-5906; CcdB-poisoned gyrase complex.
DR DIP; DIP-36179N; -.
DR IntAct; P0AES4; 55.
DR MINT; P0AES4; -.
DR STRING; 511145.b2231; -.
DR BindingDB; P0AES4; -.
DR ChEMBL; CHEMBL1858; -.
DR DrugBank; DB00537; Ciprofloxacin.
DR DrugBank; DB11943; Delafloxacin.
DR DrugCentral; P0AES4; -.
DR SWISS-2DPAGE; P0AES4; -.
DR jPOST; P0AES4; -.
DR PaxDb; P0AES4; -.
DR PRIDE; P0AES4; -.
DR EnsemblBacteria; AAC75291; AAC75291; b2231.
DR EnsemblBacteria; BAA16048; BAA16048; BAA16048.
DR GeneID; 66673880; -.
DR GeneID; 946614; -.
DR KEGG; ecj:JW2225; -.
DR KEGG; eco:b2231; -.
DR PATRIC; fig|1411691.4.peg.4; -.
DR EchoBASE; EB0418; -.
DR eggNOG; COG0188; Bacteria.
DR HOGENOM; CLU_002977_6_1_6; -.
DR InParanoid; P0AES4; -.
DR OMA; THHWLLF; -.
DR PhylomeDB; P0AES4; -.
DR BioCyc; EcoCyc:EG10423-MON; -.
DR BioCyc; MetaCyc:EG10423-MON; -.
DR EvolutionaryTrace; P0AES4; -.
DR PRO; PR:P0AES4; -.
DR Proteomes; UP000000318; Chromosome.
DR Proteomes; UP000000625; Chromosome.
DR GO; GO:0005694; C:chromosome; IEA:InterPro.
DR GO; GO:0005737; C:cytoplasm; IDA:EcoliWiki.
DR GO; GO:0005829; C:cytosol; IDA:EcoCyc.
DR GO; GO:0120217; C:DNA gyrase complex; IPI:ComplexPortal.
DR GO; GO:0009330; C:DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) complex; IBA:GO_Central.
DR GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IBA:GO_Central.
DR GO; GO:0008094; F:ATP-dependent activity, acting on DNA; IDA:EcoliWiki.
DR GO; GO:0003677; F:DNA binding; IDA:EcoliWiki.
DR GO; GO:0034335; F:DNA negative supercoiling activity; IDA:UniProtKB.
DR GO; GO:0003918; F:DNA topoisomerase type II (double strand cut, ATP-hydrolyzing) activity; IDA:CACAO.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0006265; P:DNA topological change; IDA:ComplexPortal.
DR GO; GO:0006261; P:DNA-templated DNA replication; IEA:UniProtKB-UniRule.
DR GO; GO:2000104; P:negative regulation of DNA-templated DNA replication; IDA:ComplexPortal.
DR GO; GO:0046677; P:response to antibiotic; IEA:UniProtKB-KW.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IMP:EcoliWiki.
DR GO; GO:0006351; P:transcription, DNA-templated; IDA:EcoliWiki.
DR CDD; cd00187; TOP4c; 1.
DR Gene3D; 1.10.268.10; -; 1.
DR Gene3D; 2.120.10.90; -; 1.
DR Gene3D; 3.90.199.10; -; 1.
DR HAMAP; MF_01897; GyrA; 1.
DR InterPro; IPR005743; GyrA.
DR InterPro; IPR006691; GyrA/parC_rep.
DR InterPro; IPR035516; Gyrase/topoIV_suA_C.
DR InterPro; IPR013760; Topo_IIA-like_dom_sf.
DR InterPro; IPR013758; Topo_IIA_A/C_ab.
DR InterPro; IPR013757; Topo_IIA_A_a_sf.
DR InterPro; IPR002205; Topo_IIA_dom_A.
DR Pfam; PF03989; DNA_gyraseA_C; 6.
DR Pfam; PF00521; DNA_topoisoIV; 1.
DR SMART; SM00434; TOP4c; 1.
DR SUPFAM; SSF101904; SSF101904; 1.
DR SUPFAM; SSF56719; SSF56719; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Antibiotic resistance; ATP-binding; Cytoplasm;
KW Direct protein sequencing; DNA-binding; Isomerase; Nucleotide-binding;
KW Reference proteome; Topoisomerase.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|PubMed:3029031"
FT CHAIN 2..875
FT /note="DNA gyrase subunit A"
FT /id="PRO_0000145232"
FT REGION 531..841
FT /note="C-terminal domain (CTD)"
FT /evidence="ECO:0000303|PubMed:15897198"
FT REGION 841..875
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 842..875
FT /note="Acidic tail"
FT /evidence="ECO:0000303|PubMed:22457353"
FT MOTIF 560..566
FT /note="GyrA-box"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_01897,
FT ECO:0000303|PubMed:9426128"
FT COMPBIAS 845..875
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 122
FT /note="O-(5'-phospho-DNA)-tyrosine intermediate"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_01897,
FT ECO:0000269|PubMed:3031051"
FT VARIANT 67
FT /note="A -> S (in PPA-10; quinolone-resistant)"
FT /evidence="ECO:0000269|PubMed:2168148"
FT VARIANT 81
FT /note="G -> C (in NAL-97; quinolone-resistant)"
FT /evidence="ECO:0000269|PubMed:2168148"
FT VARIANT 83
FT /note="S -> L (in NAL-51, NAL-112, NAL-118, NAL-119 and
FT strains 58, 158, 218, 231 and 235; quinolone-resistant)"
FT /evidence="ECO:0000269|PubMed:1850972,
FT ECO:0000269|PubMed:2168148"
FT VARIANT 83
FT /note="S -> W (in PPA-18 and strains 233 and 227;
FT quinolone-resistant)"
FT /evidence="ECO:0000269|PubMed:1850972,
FT ECO:0000269|PubMed:2168148, ECO:0000269|PubMed:2548439"
FT VARIANT 84
FT /note="A -> P (in PPA-05; quinolone-resistant)"
FT /evidence="ECO:0000269|PubMed:2168148"
FT VARIANT 87
FT /note="D -> N (in NAL-113 and OV6; quinolone-resistant)"
FT /evidence="ECO:0000269|PubMed:2168148,
FT ECO:0000269|PubMed:2834621"
FT VARIANT 87
FT /note="D -> V (in strain: 202; partially quinolone-
FT resistant)"
FT /evidence="ECO:0000269|PubMed:1850972"
FT VARIANT 106
FT /note="Q -> H (in NAL-89; quinolone-resistant)"
FT /evidence="ECO:0000269|PubMed:2168148"
FT VARIANT 678
FT /note="D -> E (in strain: 227)"
FT /evidence="ECO:0000269|PubMed:2548439"
FT VARIANT 798
FT /note="I -> IMMI (in strain: OV6; quinolone-resistant)"
FT /evidence="ECO:0000269|PubMed:2834621"
FT VARIANT 828
FT /note="A -> S (in strain: 227)"
FT /evidence="ECO:0000269|PubMed:2548439"
FT MUTAGEN 32
FT /note="R->A,Q: Nearly abolishes DNA supercoiling. Reduces
FT quinolone-induced DNA cleavage and relaxation."
FT /evidence="ECO:0000269|PubMed:12051842"
FT MUTAGEN 47
FT /note="R->Q: Nearly abolishes DNA supercoiling. Reduces
FT quinolone-induced DNA cleavage. Slightly reduces DNA
FT relaxation."
FT /evidence="ECO:0000269|PubMed:12051842"
FT MUTAGEN 78
FT /note="H->A: Nearly abolishes DNA supercoiling. Reduces
FT quinolone-induced DNA cleavage and DNA relaxation."
FT /evidence="ECO:0000269|PubMed:12051842"
FT MUTAGEN 80
FT /note="H->A: Reduces DNA supercoiling. Slightly reduces
FT quinolone-induced DNA cleavage. No effect on DNA
FT relaxation."
FT /evidence="ECO:0000269|PubMed:12051842"
FT MUTAGEN 83
FT /note="S->A: Resistant to fluoroquinolones."
FT /evidence="ECO:0000269|PubMed:1850970"
FT MUTAGEN 106
FT /note="Q->R: Resistant to fluoroquinolones."
FT /evidence="ECO:0000269|PubMed:1850970"
FT MUTAGEN 462
FT /note="R->C: In gyrA462; resistant to cytotoxic protein
FT CcdB, but not to the quinoline antibiotic enoxacin, has no
FT effect on DNA supercoiling. Does not interact with CcdB."
FT /evidence="ECO:0000269|PubMed:1324324,
FT ECO:0000269|PubMed:8254658"
FT MUTAGEN 560..566
FT /note="QRRGGKG->AAAAAAA: Loss of gyrase-mediated DNA
FT wrapping, nearly complete loss of DNA supercoiling
FT activity, no change in DNA supercoil relaxation or DNA
FT decatenation activity."
FT /evidence="ECO:0000269|PubMed:16332690"
FT MUTAGEN 560..566
FT /note="Missing: Loss of gyrase-mediated DNA wrapping,
FT nearly complete loss of DNA supercoiling activity, no
FT change in DNA supercoil relaxation or DNA decatenation
FT activity."
FT /evidence="ECO:0000269|PubMed:16332690"
FT MUTAGEN 842..856
FT /note="Missing: Gains ability to wrap DNA around itself in
FT the absence of GyrB; holoenzyme gains ability to wrap DNA
FT in the absence of ATP analogs, but reduces ATP-dependent
FT supercoiling activity 50-fold, DNA is not as extensively
FT negatively supercoiled, has 10-fold less ATP-independent
FT negative supercoiled DNA relaxation activity, no change in
FT ATPase activity of holoenzyme, no change in decatenation
FT ability. Isolated CTD gains ability to wrap DNA around
FT itself in the absence of GyrB, binds DNA better than wild-
FT type CTD."
FT /evidence="ECO:0000269|PubMed:22457352,
FT ECO:0000269|PubMed:22457353"
FT MUTAGEN 854..875
FT /note="Missing: Isolated CTD gains ability to wrap DNA
FT around itself in the absence of GyrB, binds DNA better than
FT wild-type CTD."
FT /evidence="ECO:0000269|PubMed:22457353"
FT TURN 31..33
FT /evidence="ECO:0007829|PDB:1AB4"
FT TURN 37..39
FT /evidence="ECO:0007829|PDB:1AB4"
FT HELIX 43..54
FT /evidence="ECO:0007829|PDB:1AB4"
FT STRAND 59..61
FT /evidence="ECO:0007829|PDB:1AB4"
FT HELIX 66..76
FT /evidence="ECO:0007829|PDB:1AB4"
FT HELIX 82..91
FT /evidence="ECO:0007829|PDB:1AB4"
FT TURN 95..97
FT /evidence="ECO:0007829|PDB:1AB4"
FT STRAND 102..107
FT /evidence="ECO:0007829|PDB:1AB4"
FT TURN 120..122
FT /evidence="ECO:0007829|PDB:1AB4"
FT STRAND 124..127
FT /evidence="ECO:0007829|PDB:1AB4"
FT HELIX 131..134
FT /evidence="ECO:0007829|PDB:1AB4"
FT TURN 136..141
FT /evidence="ECO:0007829|PDB:1AB4"
FT STRAND 145..147
FT /evidence="ECO:0007829|PDB:1AB4"
FT STRAND 151..158
FT /evidence="ECO:0007829|PDB:1AB4"
FT HELIX 165..169
FT /evidence="ECO:0007829|PDB:1AB4"
FT STRAND 171..173
FT /evidence="ECO:0007829|PDB:1AB4"
FT STRAND 180..182
FT /evidence="ECO:0007829|PDB:1AB4"
FT HELIX 187..199
FT /evidence="ECO:0007829|PDB:1AB4"
FT HELIX 205..208
FT /evidence="ECO:0007829|PDB:1AB4"
FT TURN 209..211
FT /evidence="ECO:0007829|PDB:1AB4"
FT HELIX 227..235
FT /evidence="ECO:0007829|PDB:1AB4"
FT STRAND 236..243
FT /evidence="ECO:0007829|PDB:1AB4"
FT STRAND 245..249
FT /evidence="ECO:0007829|PDB:1AB4"
FT STRAND 258..263
FT /evidence="ECO:0007829|PDB:1AB4"
FT HELIX 270..281
FT /evidence="ECO:0007829|PDB:1AB4"
FT TURN 282..284
FT /evidence="ECO:0007829|PDB:1AB4"
FT STRAND 292..294
FT /evidence="ECO:0007829|PDB:1AB4"
FT STRAND 298..300
FT /evidence="ECO:0007829|PDB:1AB4"
FT STRAND 303..305
FT /evidence="ECO:0007829|PDB:1AB4"
FT HELIX 314..323
FT /evidence="ECO:0007829|PDB:1AB4"
FT STRAND 327..333
FT /evidence="ECO:0007829|PDB:1AB4"
FT STRAND 335..338
FT /evidence="ECO:0007829|PDB:1AB4"
FT STRAND 341..344
FT /evidence="ECO:0007829|PDB:1AB4"
FT HELIX 347..388
FT /evidence="ECO:0007829|PDB:1AB4"
FT HELIX 390..399
FT /evidence="ECO:0007829|PDB:1AB4"
FT STRAND 400..402
FT /evidence="ECO:0007829|PDB:1X75"
FT HELIX 403..412
FT /evidence="ECO:0007829|PDB:1AB4"
FT HELIX 419..421
FT /evidence="ECO:0007829|PDB:1AB4"
FT STRAND 441..449
FT /evidence="ECO:0007829|PDB:1AB4"
FT HELIX 452..459
FT /evidence="ECO:0007829|PDB:1AB4"
FT HELIX 463..466
FT /evidence="ECO:0007829|PDB:1AB4"
FT HELIX 468..493
FT /evidence="ECO:0007829|PDB:1AB4"
FT HELIX 495..513
FT /evidence="ECO:0007829|PDB:1AB4"
FT STRAND 519..521
FT /evidence="ECO:0007829|PDB:1AB4"
FT STRAND 538..544
FT /evidence="ECO:0007829|PDB:1ZI0"
FT STRAND 547..553
FT /evidence="ECO:0007829|PDB:1ZI0"
FT HELIX 556..560
FT /evidence="ECO:0007829|PDB:1ZI0"
FT STRAND 578..585
FT /evidence="ECO:0007829|PDB:1ZI0"
FT STRAND 589..594
FT /evidence="ECO:0007829|PDB:1ZI0"
FT STRAND 597..603
FT /evidence="ECO:0007829|PDB:1ZI0"
FT HELIX 604..606
FT /evidence="ECO:0007829|PDB:1ZI0"
FT STRAND 612..614
FT /evidence="ECO:0007829|PDB:1ZI0"
FT HELIX 619..621
FT /evidence="ECO:0007829|PDB:1ZI0"
FT STRAND 631..638
FT /evidence="ECO:0007829|PDB:1ZI0"
FT STRAND 645..650
FT /evidence="ECO:0007829|PDB:1ZI0"
FT STRAND 653..659
FT /evidence="ECO:0007829|PDB:1ZI0"
FT HELIX 660..663
FT /evidence="ECO:0007829|PDB:1ZI0"
FT STRAND 671..674
FT /evidence="ECO:0007829|PDB:1ZI0"
FT STRAND 682..688
FT /evidence="ECO:0007829|PDB:1ZI0"
FT STRAND 693..698
FT /evidence="ECO:0007829|PDB:1ZI0"
FT STRAND 701..707
FT /evidence="ECO:0007829|PDB:1ZI0"
FT HELIX 708..710
FT /evidence="ECO:0007829|PDB:1ZI0"
FT STRAND 732..736
FT /evidence="ECO:0007829|PDB:1ZI0"
FT STRAND 743..748
FT /evidence="ECO:0007829|PDB:1ZI0"
FT STRAND 751..756
FT /evidence="ECO:0007829|PDB:1ZI0"
FT HELIX 758..760
FT /evidence="ECO:0007829|PDB:1ZI0"
FT STRAND 771..774
FT /evidence="ECO:0007829|PDB:1ZI0"
FT TURN 778..780
FT /evidence="ECO:0007829|PDB:1ZI0"
FT STRAND 782..789
FT /evidence="ECO:0007829|PDB:1ZI0"
FT STRAND 794..801
FT /evidence="ECO:0007829|PDB:1ZI0"
FT STRAND 804..808
FT /evidence="ECO:0007829|PDB:1ZI0"
FT HELIX 809..811
FT /evidence="ECO:0007829|PDB:1ZI0"
FT STRAND 833..838
FT /evidence="ECO:0007829|PDB:1ZI0"
SQ SEQUENCE 875 AA; 96964 MW; 3FD5BD52A5969069 CRC64;
MSDLAREITP VNIEEELKSS YLDYAMSVIV GRALPDVRDG LKPVHRRVLY AMNVLGNDWN
KAYKKSARVV GDVIGKYHPH GDSAVYDTIV RMAQPFSLRY MLVDGQGNFG SIDGDSAAAM
RYTEIRLAKI AHELMADLEK ETVDFVDNYD GTEKIPDVMP TKIPNLLVNG SSGIAVGMAT
NIPPHNLTEV INGCLAYIDD EDISIEGLME HIPGPDFPTA AIINGRRGIE EAYRTGRGKV
YIRARAEVEV DAKTGRETII VHEIPYQVNK ARLIEKIAEL VKEKRVEGIS ALRDESDKDG
MRIVIEVKRD AVGEVVLNNL YSQTQLQVSF GINMVALHHG QPKIMNLKDI IAAFVRHRRE
VVTRRTIFEL RKARDRAHIL EALAVALANI DPIIELIRHA PTPAEAKTAL VANPWQLGNV
AAMLERAGDD AARPEWLEPE FGVRDGLYYL TEQQAQAILD LRLQKLTGLE HEKLLDEYKE
LLDQIAELLR ILGSADRLME VIREELELVR EQFGDKRRTE ITANSADINL EDLITQEDVV
VTLSHQGYVK YQPLSEYEAQ RRGGKGKSAA RIKEEDFIDR LLVANTHDHI LCFSSRGRVY
SMKVYQLPEA TRGARGRPIV NLLPLEQDER ITAILPVTEF EEGVKVFMAT ANGTVKKTVL
TEFNRLRTAG KVAIKLVDGD ELIGVDLTSG EDEVMLFSAE GKVVRFKESS VRAMGCNTTG
VRGIRLGEGD KVVSLIVPRG DGAILTATQN GYGKRTAVAE YPTKSRATKG VISIKVTERN
GLVVGAVQVD DCDQIMMITD AGTLVRTRVS EISIVGRNTQ GVILIRTAED ENVVGLQRVA
EPVDEEDLDT IDGSAAEGDD EIAPEVDVDD EPEEE
