LOVB_ASPTE
ID LOVB_ASPTE Reviewed; 3038 AA.
AC Q9Y8A5;
DT 12-APR-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1999, sequence version 1.
DT 03-AUG-2022, entry version 121.
DE RecName: Full=Lovastatin nonaketide synthase, polyketide synthase component;
DE Short=LNKS;
DE EC=2.3.1.161 {ECO:0000269|PubMed:10334994, ECO:0000269|PubMed:10381407};
DE AltName: Full=Lovastatin biosynthesis cluster protein B {ECO:0000303|PubMed:10334994};
GN Name=lovB {ECO:0000312|EMBL:AAD39830.1};
OS Aspergillus terreus.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC Aspergillus subgen. Circumdati.
OX NCBI_TaxID=33178;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, CATALYTIC ACTIVITY, AND
RP PATHWAY.
RC STRAIN=ATCC 20542 / MF4845; TISSUE=Mycelium {ECO:0000269|PubMed:10381407};
RX PubMed=10381407; DOI=10.1016/s1074-5521(99)80061-1;
RA Hendrickson L., Davis C.R., Roach C., Nguyen D.K., Aldrich T., McAda P.C.,
RA Reeves C.D.;
RT "Lovastatin biosynthesis in Aspergillus terreus: characterization of
RT blocked mutants, enzyme activities and a multifunctional polyketide
RT synthase gene.";
RL Chem. Biol. 6:429-439(1999).
RN [2]
RP BIOTECHNOLOGY.
RX PubMed=6933445; DOI=10.1073/pnas.77.7.3957;
RA Alberts A.W., Chen J., Kuron G., Hunt V., Huff J., Hoffman C., Rothrock J.,
RA Lopez M., Joshua H., Harris E., Patchett A., Monaghan R., Currie S.,
RA Stapley E., Albers-Schonberg G., Hensens O., Hirshfield J., Hoogsteen K.,
RA Liesch J., Springer J.;
RT "Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-
RT coenzyme A reductase and a cholesterol-lowering agent.";
RL Proc. Natl. Acad. Sci. U.S.A. 77:3957-3961(1980).
RN [3]
RP FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY.
RX PubMed=10334994; DOI=10.1126/science.284.5418.1368;
RA Kennedy J., Auclair K., Kendrew S.G., Park C., Vederas J.C.,
RA Hutchinson C.R.;
RT "Modulation of polyketide synthase activity by accessory proteins during
RT lovastatin biosynthesis.";
RL Science 284:1368-1372(1999).
RN [4]
RP FUNCTION.
RX PubMed=12929390; DOI=10.1039/b207721c;
RA Sorensen J.L., Auclair K., Kennedy J., Hutchinson C.R., Vederas J.C.;
RT "Transformations of cyclic nonaketides by Aspergillus terreus mutants
RT blocked for lovastatin biosynthesis at the lovA and lovC genes.";
RL Org. Biomol. Chem. 1:50-59(2003).
RN [5]
RP FUNCTION.
RX PubMed=17113998; DOI=10.1016/j.chembiol.2006.09.008;
RA Xie X., Watanabe K., Wojcicki W.A., Wang C.C., Tang Y.;
RT "Biosynthesis of lovastatin analogs with a broadly specific
RT acyltransferase.";
RL Chem. Biol. 13:1161-1169(2006).
RN [6]
RP FUNCTION.
RX PubMed=18988191; DOI=10.1002/bit.22028;
RA Xie X., Pashkov I., Gao X., Guerrero J.L., Yeates T.O., Tang Y.;
RT "Rational improvement of simvastatin synthase solubility in Escherichia
RT coli leads to higher whole-cell biocatalytic activity.";
RL Biotechnol. Bioeng. 102:20-28(2009).
RN [7]
RP FUNCTION.
RX PubMed=19875080; DOI=10.1016/j.chembiol.2009.09.017;
RA Gao X., Xie X., Pashkov I., Sawaya M.R., Laidman J., Zhang W., Cacho R.,
RA Yeates T.O., Tang Y.;
RT "Directed evolution and structural characterization of a simvastatin
RT synthase.";
RL Chem. Biol. 16:1064-1074(2009).
RN [8]
RP FUNCTION.
RX PubMed=19530726; DOI=10.1021/ja903203g;
RA Xie X., Meehan M.J., Xu W., Dorrestein P.C., Tang Y.;
RT "Acyltransferase mediated polyketide release from a fungal megasynthase.";
RL J. Am. Chem. Soc. 131:8388-8389(2009).
RN [9]
RP FUNCTION, PATHWAY, COFACTOR, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=19900898; DOI=10.1126/science.1175602;
RA Ma S.M., Li J.W., Choi J.W., Zhou H., Lee K.K., Moorthie V.A., Xie X.,
RA Kealey J.T., Da Silva N.A., Vederas J.C., Tang Y.;
RT "Complete reconstitution of a highly reducing iterative polyketide
RT synthase.";
RL Science 326:589-592(2009).
RN [10]
RP FUNCTION.
RX PubMed=21069965; DOI=10.1021/bi1014776;
RA Meehan M.J., Xie X., Zhao X., Xu W., Tang Y., Dorrestein P.C.;
RT "FT-ICR-MS characterization of intermediates in the biosynthesis of the
RT alpha-methylbutyrate side chain of lovastatin by the 277 kDa polyketide
RT synthase LovF.";
RL Biochemistry 50:287-299(2011).
RN [11]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, AND BIOPHYSICOCHEMICAL
RP PROPERTIES.
RX PubMed=21495633; DOI=10.1021/ja201138v;
RA Barriuso J., Nguyen D.T., Li J.W., Roberts J.N., MacNevin G., Chaytor J.L.,
RA Marcus S.L., Vederas J.C., Ro D.K.;
RT "Double oxidation of the cyclic nonaketide dihydromonacolin L to monacolin
RT J by a single cytochrome P450 monooxygenase, LovA.";
RL J. Am. Chem. Soc. 133:8078-8081(2011).
RN [12]
RP FUNCTION, CATALYTIC ACTIVITY, AND DOMAIN.
RX PubMed=23023987; DOI=10.1002/cbic.201200449;
RA Boettger D., Bergmann H., Kuehn B., Shelest E., Hertweck C.;
RT "Evolutionary imprint of catalytic domains in fungal PKS-NRPS hybrids.";
RL ChemBioChem 13:2363-2373(2012).
RN [13]
RP FUNCTION, INTERACTION WITH LOVC, AND DOMAIN.
RX PubMed=22733743; DOI=10.1073/pnas.1113029109;
RA Ames B.D., Nguyen C., Bruegger J., Smith P., Xu W., Ma S., Wong E.,
RA Wong S., Xie X., Li J.W., Vederas J.C., Tang Y., Tsai S.C.;
RT "Crystal structure and biochemical studies of the trans-acting polyketide
RT enoyl reductase LovC from lovastatin biosynthesis.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:11144-11149(2012).
RN [14]
RP FUNCTION, AND DOMAIN.
RX PubMed=23653178; DOI=10.1002/anie.201302406;
RA Xu W., Chooi Y.H., Choi J.W., Li S., Vederas J.C., Da Silva N.A., Tang Y.;
RT "LovG: the thioesterase required for dihydromonacolin L release and
RT lovastatin nonaketide synthase turnover in lovastatin biosynthesis.";
RL Angew. Chem. Int. Ed. Engl. 52:6472-6475(2013).
RN [15]
RP FUNCTION.
RX PubMed=24727900; DOI=10.1038/nchembio.1503;
RA Jimenez-Oses G., Osuna S., Gao X., Sawaya M.R., Gilson L., Collier S.J.,
RA Huisman G.W., Yeates T.O., Tang Y., Houk K.N.;
RT "The role of distant mutations and allosteric regulation on LovD active
RT site dynamics.";
RL Nat. Chem. Biol. 10:431-436(2014).
RN [16]
RP BIOTECHNOLOGY.
RX PubMed=29236027; DOI=10.3390/ijms18122690;
RA Chen M.C., Tsai Y.C., Tseng J.H., Liou J.J., Horng S., Wen H.C., Fan Y.C.,
RA Zhong W.B., Hsu S.P.;
RT "Simvastatin inhibits cell proliferation and migration in human anaplastic
RT thyroid cancer.";
RL Int. J. Mol. Sci. 18:0-0(2017).
RN [17]
RP BIOTECHNOLOGY.
RX PubMed=29932104; DOI=10.3390/ijms19071834;
RA Zhong W.B., Tsai Y.C., Chin L.H., Tseng J.H., Tang L.W., Horng S.,
RA Fan Y.C., Hsu S.P.;
RT "A synergistic anti-cancer effect of troglitazone and lovastatin in a human
RT anaplastic thyroid cancer cell line and in a mouse xenograft model.";
RL Int. J. Mol. Sci. 19:0-0(2018).
CC -!- FUNCTION: Lovastatin nonaketide synthase; part of the gene cluster that
CC mediates the biosynthesis of lovastatin (also known as mevinolin,
CC mevacor or monacolin K), a hypolipidemic inhibitor of (3S)-
CC hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR)
CC (PubMed:10334994, PubMed:12929390, PubMed:21495633, PubMed:23023987).
CC The first step in the biosynthesis of lovastatin is the production of
CC dihydromonacolin L acid by the lovastatin nonaketide synthase lovB and
CC the trans-acting enoyl reductase lovC via condensation of one acetyl-
CC CoA unit and 8 malonyl-CoA units (PubMed:10334994, PubMed:10381407,
CC PubMed:19900898, PubMed:23023987, PubMed:22733743). Dihydromonacolin L
CC acid is released from lovB by the thioesterase lovG (PubMed:23653178).
CC Next, dihydromonacolin L acid is oxidized by the dihydromonacolin L
CC monooxygenase lovA twice to form monacolin J acid (PubMed:12929390,
CC PubMed:21495633). The 2-methylbutyrate moiety of lovastatin is
CC synthesized by the lovastatin diketide synthase lovF via condensation
CC of one acetyl-CoA unit and one malonyl-CoA unit (PubMed:19530726,
CC PubMed:21069965). Finally, the covalent attachment of this moiety to
CC monacolin J acid is catalyzed by the transesterase lovD to yield
CC lovastatin (PubMed:10334994, PubMed:17113998, PubMed:18988191,
CC PubMed:19875080, PubMed:24727900). LovD has broad substrate specificity
CC and can also convert monacolin J to simvastatin using alpha-
CC dimethylbutanoyl-S-methyl-3-mercaptopropionate (DMB-S-MMP) as the
CC thioester acyl donor, and can also catalyze the reverse reaction and
CC function as hydrolase in vitro (PubMed:19875080). LovD has much higher
CC activity with LovF-bound 2-methylbutanoate than with free diketide
CC substrates (PubMed:21069965). {ECO:0000269|PubMed:10334994,
CC ECO:0000269|PubMed:10381407, ECO:0000269|PubMed:12929390,
CC ECO:0000269|PubMed:17113998, ECO:0000269|PubMed:18988191,
CC ECO:0000269|PubMed:19530726, ECO:0000269|PubMed:19875080,
CC ECO:0000269|PubMed:19900898, ECO:0000269|PubMed:21069965,
CC ECO:0000269|PubMed:21495633, ECO:0000269|PubMed:22733743,
CC ECO:0000269|PubMed:23023987, ECO:0000269|PubMed:23653178,
CC ECO:0000269|PubMed:24727900}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=19 H(+) + holo-[lovastatin nonaketide synthase] + 9 malonyl-
CC CoA + 11 NADPH + S-adenosyl-L-methionine = 9 CO2 + 9 CoA +
CC dihydromonacolin L-[lovastatin nonaketide synthase] + 6 H2O + 11
CC NADP(+) + S-adenosyl-L-homocysteine; Xref=Rhea:RHEA:18565, Rhea:RHEA-
CC COMP:10042, Rhea:RHEA-COMP:10043, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16526, ChEBI:CHEBI:57287,
CC ChEBI:CHEBI:57384, ChEBI:CHEBI:57783, ChEBI:CHEBI:57856,
CC ChEBI:CHEBI:58349, ChEBI:CHEBI:59789, ChEBI:CHEBI:64479,
CC ChEBI:CHEBI:79032; EC=2.3.1.161;
CC Evidence={ECO:0000269|PubMed:10334994, ECO:0000269|PubMed:10381407,
CC ECO:0000269|PubMed:23023987};
CC -!- COFACTOR:
CC Name=pantetheine 4'-phosphate; Xref=ChEBI:CHEBI:47942;
CC Evidence={ECO:0000269|PubMed:19900898};
CC Note=Binds 1 phosphopantetheine covalently.
CC {ECO:0000269|PubMed:19900898};
CC -!- PATHWAY: Polyketide biosynthesis; lovastatin biosynthesis.
CC {ECO:0000269|PubMed:10334994, ECO:0000269|PubMed:10381407,
CC ECO:0000269|PubMed:19900898}.
CC -!- SUBUNIT: Interacts with LovC. {ECO:0000269|PubMed:22733743}.
CC -!- DOMAIN: Multidomain protein; including a ketosynthase (KS) that
CC catalyzes repeated decarboxylative condensation to elongate the
CC polyketide backbone; a malonyl-CoA:ACP transacylase (MAT) that selects
CC and transfers the extender unit malonyl-CoA; a dehydratase (DH) domain
CC that reduces hydroxyl groups to enoyl groups; a methyltransferase
CC (CMeT) domain responsible for the incorporation of methyl groups; a
CC ketoreductase (KR) domain that catalyzes beta-ketoreduction steps; and
CC an acyl-carrier protein (ACP) that serves as the tether of the growing
CC and completed polyketide via its phosphopantetheinyl arm
CC (PubMed:22733743). A C-terminal thioesterase (TE) domain that is often
CC found in polyketide synthase proteins is not present in this protein,
CC but lovB contains insteado a C-terminal condensation (C) domain that
CC has lost its condensation activity, but has gained a novel function
CC that is necessary for release of the final product (PubMed:23023987).
CC {ECO:0000269|PubMed:22733743, ECO:0000269|PubMed:23023987}.
CC -!- DOMAIN: Lacks an enoylreductase (ER) domain that reduces enoyl groups
CC to alkyl group which function is performed by the trans-acting enoyl
CC reductase lovC. {ECO:0000269|PubMed:22733743}.
CC -!- BIOTECHNOLOGY: Lovastatin acts as a hypolipidemic agent that works as
CC inhibitor of (3S)-hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase
CC (HMGR) which reduces HMG-CoA to mevalonate and is the key step in
CC cholesterol biosynthesis (PubMed:6933445). Lovastatin, simvastatin and
CC related compounds are widely used to treat hypercholesteremia and
CC reduce the risk of cardiovascular disease (PubMed:6933445).
CC Furthermore, statins such as lovastatin were found to be anticancer
CC agents (PubMed:29236027, PubMed:29932104).
CC {ECO:0000269|PubMed:29236027, ECO:0000269|PubMed:29932104,
CC ECO:0000269|PubMed:6933445}.
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DR EMBL; AF151722; AAD39830.1; -; Genomic_DNA.
DR PDB; 7CPX; EM; 2.91 A; A/B=1-3038.
DR PDB; 7CPY; EM; 3.60 A; A/B=1-3038.
DR PDBsum; 7CPX; -.
DR PDBsum; 7CPY; -.
DR SMR; Q9Y8A5; -.
DR DIP; DIP-60051N; -.
DR IntAct; Q9Y8A5; 1.
DR KEGG; ag:AAD39830; -.
DR VEuPathDB; FungiDB:ATEG_09961; -.
DR BioCyc; MetaCyc:MON-18782; -.
DR BRENDA; 2.3.1.161; 536.
DR UniPathway; UPA00875; -.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR GO; GO:0016747; F:acyltransferase activity, transferring groups other than amino-acyl groups; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; NAS:UniProtKB.
DR GO; GO:0050637; F:lovastatin nonaketide synthase activity; IDA:UniProtKB.
DR GO; GO:0016491; F:oxidoreductase activity; IDA:UniProtKB.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0008757; F:S-adenosylmethionine-dependent methyltransferase activity; IDA:UniProtKB.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:InterPro.
DR GO; GO:2001293; P:malonyl-CoA metabolic process; IDA:UniProtKB.
DR GO; GO:0032259; P:methylation; IDA:UniProtKB.
DR GO; GO:0070995; P:NADPH oxidation; IDA:UniProtKB.
DR GO; GO:0030639; P:polyketide biosynthetic process; IDA:UniProtKB.
DR GO; GO:0046500; P:S-adenosylmethionine metabolic process; IDA:UniProtKB.
DR Gene3D; 3.10.129.110; -; 1.
DR Gene3D; 3.30.559.10; -; 1.
DR Gene3D; 3.40.366.10; -; 1.
DR Gene3D; 3.40.47.10; -; 1.
DR Gene3D; 3.40.50.150; -; 1.
DR InterPro; IPR001227; Ac_transferase_dom_sf.
DR InterPro; IPR036736; ACP-like_sf.
DR InterPro; IPR014043; Acyl_transferase.
DR InterPro; IPR016035; Acyl_Trfase/lysoPLipase.
DR InterPro; IPR023213; CAT-like_dom_sf.
DR InterPro; IPR001242; Condensatn.
DR InterPro; IPR018201; Ketoacyl_synth_AS.
DR InterPro; IPR014031; Ketoacyl_synth_C.
DR InterPro; IPR014030; Ketoacyl_synth_N.
DR InterPro; IPR016036; Malonyl_transacylase_ACP-bd.
DR InterPro; IPR013217; Methyltransf_12.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR032821; PKS_assoc.
DR InterPro; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR InterPro; IPR020807; PKS_dehydratase.
DR InterPro; IPR042104; PKS_dehydratase_sf.
DR InterPro; IPR013968; PKS_KR.
DR InterPro; IPR020806; PKS_PP-bd.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF00668; Condensation; 1.
DR Pfam; PF16197; KAsynt_C_assoc; 1.
DR Pfam; PF00109; ketoacyl-synt; 1.
DR Pfam; PF02801; Ketoacyl-synt_C; 1.
DR Pfam; PF08659; KR; 1.
DR Pfam; PF08242; Methyltransf_12; 1.
DR Pfam; PF14765; PS-DH; 1.
DR SMART; SM00827; PKS_AT; 1.
DR SMART; SM00826; PKS_DH; 1.
DR SMART; SM00825; PKS_KS; 1.
DR SMART; SM00823; PKS_PP; 1.
DR SUPFAM; SSF47336; SSF47336; 1.
DR SUPFAM; SSF51735; SSF51735; 2.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS50075; CARRIER; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acyltransferase; Methyltransferase; Multifunctional enzyme;
KW NADP; Oxidoreductase; Phosphopantetheine; Phosphoprotein;
KW S-adenosyl-L-methionine; Transferase.
FT CHAIN 1..3038
FT /note="Lovastatin nonaketide synthase, polyketide synthase
FT component"
FT /id="PRO_0000180288"
FT DOMAIN 2463..2538
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:22733743"
FT REGION 11..450
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:22733743"
FT REGION 562..889
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:22733743"
FT REGION 953..1263
FT /note="Dehydrogenase (DH) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:22733743"
FT REGION 1443..1543
FT /note="Methyltransferase (CMet) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:22733743"
FT REGION 2139..2437
FT /note="Ketoreductase (KR) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:22733743"
FT REGION 2546..2602
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2602..2952
FT /note="Inactive Condensation domain"
FT /evidence="ECO:0000269|PubMed:23023987"
FT ACT_SITE 181
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 656
FT /note="For malonyltransferase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 985
FT /note="For beta-hydroxyacyl dehydratase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 2498
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT STRAND 6..8
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 11..20
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 21..23
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 27..35
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 46..48
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 51..53
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 69..71
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 82..86
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 89..94
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 97..113
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 117..120
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 126..131
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 136..141
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 142..144
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 151..155
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 159..168
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 174..177
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 180..182
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 183..196
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 203..209
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 214..222
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 247..255
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 256..261
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 267..277
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 282..285
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 289..302
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 310..312
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 315..318
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 327..339
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 356..358
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 361..363
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 369..386
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 396..398
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 400..402
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 403..405
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 428..435
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 436..438
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 439..446
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 475..481
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 482..498
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 504..513
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 519..524
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 529..542
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 558..563
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 571..574
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 575..578
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 582..596
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 600..602
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 608..612
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 615..617
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 624..644
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 648..652
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 657..665
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 671..682
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 765..767
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 768..780
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 800..804
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 809..812
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 815..820
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 828..838
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 839..841
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 844..850
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 855..865
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 866..868
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 872..877
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 879..881
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 883..898
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 900..902
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 905..911
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 921..923
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 941..947
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 948..950
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 954..956
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 957..959
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 965..974
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 976..978
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 980..984
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 990..992
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 995..1012
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1016..1027
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1032..1035
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1040..1052
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 1053..1056
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1057..1069
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1075..1087
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1113..1115
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1117..1126
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1133..1136
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1140..1144
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1147..1152
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 1160..1162
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1170..1184
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 1187..1189
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1196..1206
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1208..1217
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1222..1230
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1232..1243
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1249..1262
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1266..1268
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1274..1282
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1285..1287
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1290..1292
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1298..1309
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1313..1324
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 1325..1329
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1330..1333
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1339..1354
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 1355..1360
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1361..1370
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1372..1375
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1376..1386
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1389..1393
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 1399..1402
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1409..1415
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 1417..1419
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1420..1436
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1439..1445
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1451..1457
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1464..1469
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1474..1476
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1477..1483
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 1486..1490
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1491..1493
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1503..1505
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1512..1519
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1521..1523
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1527..1537
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1538..1547
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1554..1561
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 1565..1567
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1571..1573
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1574..1578
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1583..1592
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1600..1602
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1605..1608
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 1610..1612
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1614..1618
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1644..1647
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1652..1664
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1670..1675
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1676..1680
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1689..1693
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 1695..1697
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1701..1703
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1705..1707
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1709..1719
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1720..1729
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 1730..1733
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1735..1750
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1754..1762
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1775..1784
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1797..1801
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1804..1811
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1814..1822
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1828..1832
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 1833..1835
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1838..1842
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1849..1853
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 1863..1867
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1869..1876
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1878..1883
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 1884..1886
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1887..1898
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1901..1911
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1913..1918
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1920..1922
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1935..1953
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1963..1969
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 1972..1985
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 1988..1993
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 2018..2024
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 2031..2034
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 2041..2051
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 2057..2059
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 2061..2064
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 2065..2067
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 2085..2095
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 2096..2098
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 2099..2101
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 2106..2110
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 2111..2117
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 2120..2122
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 2128..2130
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 2135..2138
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 2139..2143
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 2157..2162
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 2167..2178
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 2183..2187
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 2195..2203
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 2207..2210
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 2218..2230
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 2236..2241
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 2251..2253
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 2256..2276
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 2282..2284
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 2287..2294
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 2296..2299
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 2305..2323
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 2329..2333
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 2335..2340
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 2341..2344
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 2348..2353
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 2354..2357
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 2363..2385
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 2393..2395
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 2397..2399
FT /evidence="ECO:0007829|PDB:7CPX"
FT STRAND 2400..2402
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 2410..2412
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 2413..2415
FT /evidence="ECO:0007829|PDB:7CPX"
FT TURN 2417..2420
FT /evidence="ECO:0007829|PDB:7CPX"
FT HELIX 2422..2427
FT /evidence="ECO:0007829|PDB:7CPX"
SQ SEQUENCE 3038 AA; 335005 MW; 1A944375E05DF403 CRC64;
MAQSMYPNEP IVVVGSGCRF PGDANTPSKL WELLQHPRDV QSRIPKERFD VDTFYHPDGK
HHGRTNAPYA YVLQDDLGAF DAAFFNIQAG EAESMDPQHR LLLETVYEAV TNAGMRIQDL
QGTSTAVYVG VMTHDYETVS TRDLESIPTY SATGVAVSVA SNRISYFFDW HGPSMTIDTA
CSSSLVAVHL AVQQLRTGQS SMAIAAGANL ILGPMTFVLE SKLSMLSPSG RSRMWDAGAD
GYARGEAVCS VVLKTLSQAL RDGDTIECVI RETGVNQDGR TTGITMPNHS AQEALIKATY
AQAGLDITKA EDRCQFFEAH GTGTPAGDPQ EAEAIATAFF GHEQVARSDG NERAPLFVGS
AKTVVGHTEG TAGLAGLMKA SFAVRHGVIP PNLLFDKISP RVAPFYKNLR IPTEATQWPA
LPPGQPRRAS VNSFGFGGTN AHAIIEEYME PEQNQLRVSN NEDCPPMTGV LSLPLVLSAK
SQRSLKIMME EMLQFLQSHP EIHLHDLTWS LLRKRSVLPF RRAIVGHSHE TIRRALEDAI
EDGIVSSDFT TEVRGQPSVL GIFTGQGAQW PGMLKNLIEA SPYVRNIVRE LDDSLQSLPE
KYRPSWTLLD QFMLEGEASN VQYATFSQPL CCAVQIVLVR LLEAARIRFT AVVGHSSGEI
ACAFAAGLIS ASLAIRIAYL RGVVSAGGAR GTPGAMLAAG MSFEEAQEIC ELDAFEGRIC
VAASNSPDSV TFSGDANAID HLKGMLEDES TFARLLKVDT AYHSHHMLPC ADPYMQALEE
CGCAVADAGS PAGSVPWYSS VDAENRQMAA RDVTAKYWKD NLVSPVLFSH AVQRAVVTHK
ALDIGIEVGC HPALKSPCVA TIKDVLSGVD LAYTGCLERG KNDLDSFSRA LAYLWERFGA
SSFDADEFMR AVAPDRPCMS VSKLLPAYPW DRSRRYWVES RATRHHLRGP KPHLLLGKLS
EYSTPLSFQW LNFVRPRDIE WLDGHALQGQ TVFPAAGYIV MAMEAALMIA GTHAKQVKLL
EILDMSIDKA VIFDDEDSLV ELNLTADVSR NAGEAGSMTI SFKIDSCLSK EGNLSLSAKG
QLALTIEDVN PRTTSASDQH HLPPPEEEHP HMNRVNINAF YHELGLMGYN YSKDFRRLHN
MQRADLRASG TLDFIPLMDE GNGCPLLLHP ASLDVAFQTV IGAYSSPGDR RLRCLYVPTH
VDRITLVPSL CLATAESGCE KVAFNTINTY DKGDYLSGDI VVFDAEQTTL FQVENITFKP
FSPPDASTDH AMFARWSWGP LTPDSLLDNP EYWATAQDKE AIPIIERIVY FYIRSFLSQL
TLEERQQAAF HLQKQIEWLE QVLASAKEGR HLWYDPGWEN DTEAQIEHLC TANSYHPHVR
LVQRVGQHLL PTVRSNGNPF DLLDHDGLLT EFYTNTLSFG PALHYARELV AQIAHRYQSM
DILEIGAGTG GATKYVLATP QLGFNSYTYT DISTGFFEQA REQFAPFEDR MVFEPLDIRR
SPAEQGFEPH AYDLIIASNV LHATPDLEKT MAHARSLLKP GGQMVILEIT HKEHTRLGFI
FGLFADWWAG VDDGRCTEPF VSFDRWDAIL KRVGFSGVDS RTTDRDANLF PTSVFSTHAI
DATVEYLDAP LASSGTVKDS YPPLVVVGGQ TPQSQRLLND IKAIMPPRPL QTYKRLVDLL
DAEELPMKST FVMLTELDEE LFAGLTEETF EATKLLLTYA SNTVWLTENA WVQHPHQAST
IGMLRSIRRE HPDLGVHVLD VDAVETFDAT FLVEQVLRLE EHTDELASST TWTQEPEVSW
CKGRPWIPRL KRDLARNNRM NSSRRPIYEM IDSSRAPVAL QTARDSSSYF LESAETWFVP
ESVQQMETKT IYVHFSCPHA LRVGQLGFFY LVQGHVQEGN REVPVVALAE RNASIVHVRP
DYIYTEADNN LSEGGGSLMV TVLAAAVLAE TVISTAKCLG VTDSILVLNP PSICGQMLLH
AGEEIGLQVH LATTSGNRSS VSAGDAKSWL TLHARDTDWH LRRVLPRGVQ ALVDLSADQS
CEGLTQRMMK VLMPGCAHYR AADLFTDTVS TELHSGSRHQ ASLPAAYWEH VVSLARQGLP
SVSEGWEVMP CTQFAAHADK TRPDLSTVIS WPRESDEATL PTRVRSIDAE TLFAADKTYL
LVGLTGDLGR SLGRWMVQHG ACHIVLTSRN PQVNPKWLAH VEELGGRVTV LSMDVTSQNS
VEAGLAKLKD LHLPPVGGIA FGPLVLQDVM LNNMELPMME MVLNPKVEGV RILHEKFSDP
TSSNPLDFFV MFSSIVAVMG NPGQANYSAA NCYLQALAQQ RVASGLAAST IDIGAVYGVG
FVTRAELEED FNAIRFMFDS VEEHELHTLF AEAVVAGRRA VHQQEQQRKF ATVLDMADLE
LTTGIPPLDP ALKDRITFFD DPRIGNLKIP EYRGAKAGEG AAGSKGSVKE QLLQATNLDQ
VRQIVIDGLS AKLQVTLQIP DGESVHPTIP LIDQGVDSLG AVTVGTWFSK QLYLDLPLLK
VLGGASITDL ANEAAARLPP SSIPLVAATD GGAESTDNTS ENEVSGREDT DLSAAATITE
PSSADEDDTE PGDEDVPRSH HPLSLGQEYS WRIQQGAEDP TVFNNTIGMF MKGSIDLKRL
YKALRAVLRR HEIFRTGFAN VDENGMAQLV FGQTKNKVQT IQVSDRAGAE EGYRQLVQTR
YNPAAGDTLR LVDFFWGQDD HLLVVAYHRL VGDGSTTENI FVEAGQLYDG TSLSPHVPQF
ADLAARQRAM LEDGRMEEDL AYWKKMHYRP SSIPVLPLMR PLVGNSSRSD TPNFQHCGPW
QQHEAVARLD PMVAFRIKER SRKHKATPMQ FYLAAYQVLL ARLTDSTDLT VGLADTNRAT
VDEMAAMGFF ANLLPLRFRD FRPHITFGEH LIATRDLVRE ALQHARVPYG VLLDQLGLEV
PVPTSNQPAP LFQAVFDYKQ GQAESGTIGG AKITEVIATR ERTPYDVVLE MSDDPTKDPL
LTAKLQSSRY EAHHPQAFLE SYMSLLSMFS MNPALKLA
