MMPL3_MYCS2
ID MMPL3_MYCS2 Reviewed; 1013 AA.
AC A0QP27; I7G2R2;
DT 02-JUN-2021, integrated into UniProtKB/Swiss-Prot.
DT 09-JAN-2007, sequence version 1.
DT 03-AUG-2022, entry version 100.
DE RecName: Full=Trehalose monomycolate exporter MmpL3 {ECO:0000305};
DE Short=TMM exporter MmpL3 {ECO:0000305};
DE AltName: Full=MmpL3 transporter {ECO:0000303|PubMed:31113875};
DE AltName: Full=Mycobacterial membrane protein large 3 {ECO:0000303|PubMed:28698380, ECO:0000303|PubMed:30682372, ECO:0000303|PubMed:31113875, ECO:0000303|PubMed:31239378, ECO:0000303|PubMed:32512002};
GN Name=mmpL3 {ECO:0000303|PubMed:22520756, ECO:0000303|PubMed:28698380,
GN ECO:0000303|PubMed:28703701, ECO:0000303|PubMed:30682372,
GN ECO:0000303|PubMed:31113875, ECO:0000303|PubMed:31239378,
GN ECO:0000303|PubMed:32512002, ECO:0000312|EMBL:AFP36724.1};
GN OrderedLocusNames=MSMEG_0250 {ECO:0000312|EMBL:ABK74656.1},
GN MSMEI_0243 {ECO:0000312|EMBL:AFP36724.1};
OS Mycolicibacterium smegmatis (strain ATCC 700084 / mc(2)155) (Mycobacterium
OS smegmatis).
OC Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae;
OC Mycolicibacterium.
OX NCBI_TaxID=246196 {ECO:0000312|EMBL:ABK74656.1};
RN [1] {ECO:0000312|EMBL:ABK74656.1, ECO:0000312|Proteomes:UP000000757}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 700084 / mc(2)155 {ECO:0000312|Proteomes:UP000000757};
RA Fleischmann R.D., Dodson R.J., Haft D.H., Merkel J.S., Nelson W.C.,
RA Fraser C.M.;
RL Submitted (OCT-2006) to the EMBL/GenBank/DDBJ databases.
RN [2] {ECO:0000312|EMBL:AFP36724.1, ECO:0000312|Proteomes:UP000006158}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 700084 / mc(2)155 {ECO:0000312|Proteomes:UP000006158};
RX PubMed=17295914; DOI=10.1186/gb-2007-8-2-r20;
RA Deshayes C., Perrodou E., Gallien S., Euphrasie D., Schaeffer C.,
RA Van-Dorsselaer A., Poch O., Lecompte O., Reyrat J.-M.;
RT "Interrupted coding sequences in Mycobacterium smegmatis: authentic
RT mutations or sequencing errors?";
RL Genome Biol. 8:R20.1-R20.9(2007).
RN [3] {ECO:0000312|EMBL:AFP36724.1, ECO:0000312|Proteomes:UP000006158}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 700084 / mc(2)155 {ECO:0000312|Proteomes:UP000006158};
RX PubMed=18955433; DOI=10.1101/gr.081901.108;
RA Gallien S., Perrodou E., Carapito C., Deshayes C., Reyrat J.-M.,
RA Van Dorsselaer A., Poch O., Schaeffer C., Lecompte O.;
RT "Ortho-proteogenomics: multiple proteomes investigation through orthology
RT and a new MS-based protocol.";
RL Genome Res. 19:128-135(2009).
RN [4]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RC STRAIN=ATCC 700084 / mc(2)155 {ECO:0000303|PubMed:22520756};
RX PubMed=22520756; DOI=10.1016/j.chembiol.2012.03.006;
RA Varela C., Rittmann D., Singh A., Krumbach K., Bhatt K., Eggeling L.,
RA Besra G.S., Bhatt A.;
RT "MmpL genes are associated with mycolic acid metabolism in mycobacteria and
RT corynebacteria.";
RL Chem. Biol. 19:498-506(2012).
RN [5]
RP FUNCTION, AND VARIANTS CYS-257; ALA-293; THR-293; PHE-297 AND ASP-750.
RX PubMed=28703701; DOI=10.1099/mic.0.000498;
RA McNeil M.B., Dennison D., Parish T.;
RT "Mutations in MmpL3 alter membrane potential, hydrophobicity and antibiotic
RT susceptibility in Mycobacterium smegmatis.";
RL Microbiology 163:1065-1070(2017).
RN [6]
RP FUNCTION, ACTIVITY REGULATION, SUBCELLULAR LOCATION, BIOTECHNOLOGY, AND
RP VARIANTS MET-197 AND THR-326.
RC STRAIN=ATCC 700084 / mc(2)155 {ECO:0000303|PubMed:28698380};
RX PubMed=28698380; DOI=10.1073/pnas.1700062114;
RA Xu Z., Meshcheryakov V.A., Poce G., Chng S.S.;
RT "MmpL3 is the flippase for mycolic acids in mycobacteria.";
RL Proc. Natl. Acad. Sci. U.S.A. 114:7993-7998(2017).
RN [7]
RP FUNCTION, INTERACTION WITH TTFA AND MSMEG_5308, SUBCELLULAR LOCATION,
RP IDENTIFICATION BY MASS SPECTROMETRY, AND DISRUPTION PHENOTYPE.
RC STRAIN=ATCC 700084 / mc(2)155 {ECO:0000303|PubMed:31239378};
RX PubMed=31239378; DOI=10.1128/mbio.00850-19;
RA Fay A., Czudnochowski N., Rock J.M., Johnson J.R., Krogan N.J.,
RA Rosenberg O., Glickman M.S.;
RT "Two Accessory Proteins Govern MmpL3 Mycolic Acid Transport in
RT Mycobacteria.";
RL MBio 10:E00850-E00850(2019).
RN [8] {ECO:0007744|PDB:6AJF, ECO:0007744|PDB:6AJG, ECO:0007744|PDB:6AJH, ECO:0007744|PDB:6AJI, ECO:0007744|PDB:6AJJ}
RP X-RAY CRYSTALLOGRAPHY (2.60 ANGSTROMS) OF 1-748 AND IN COMPLEXES WITH
RP INHIBITORS AU1235; ICA38 AND RIMONABANT AND ANTITUBERCULAR DRUG SQ109,
RP ACTIVITY REGULATION, SUBUNIT, SUBCELLULAR LOCATION, BIOTECHNOLOGY,
RP TOPOLOGY, SITES, VARIANTS CYS-257; ALA-293; THR-293 AND PHE-297, AND
RP MUTAGENESIS OF GLN-40; ILE-194; SER-301; THR-316; ILE-319; ILE-572;
RP SER-596; VAL-638; LEU-686; VAL-688; VAL-689 AND ALA-705.
RC STRAIN=ATCC 700084 / mc(2)155 {ECO:0000303|PubMed:30682372};
RX PubMed=30682372; DOI=10.1016/j.cell.2019.01.003;
RA Zhang B., Li J., Yang X., Wu L., Zhang J., Yang Y., Zhao Y., Zhang L.,
RA Yang X., Yang X., Cheng X., Liu Z., Jiang B., Jiang H., Guddat L.W.,
RA Yang H., Rao Z.;
RT "Crystal Structures of Membrane Transporter MmpL3, an Anti-TB Drug
RT Target.";
RL Cell 176:636-648.e13(2019).
RN [9] {ECO:0007744|PDB:6N40, ECO:0007744|PDB:6OR2}
RP X-RAY CRYSTALLOGRAPHY (2.59 ANGSTROMS) OF 1-773 AND IN COMPLEX WITH
RP PHOSPHATIDYLETHANOLAMINE, FUNCTION, SUBUNIT, SUBCELLULAR LOCATION,
RP TOPOLOGY, AND SITES.
RC STRAIN=ATCC 700084 / mc(2)155 {ECO:0000303|PubMed:31113875};
RX PubMed=31113875; DOI=10.1073/pnas.1901346116;
RA Su C.C., Klenotic P.A., Bolla J.R., Purdy G.E., Robinson C.V., Yu E.W.;
RT "MmpL3 is a lipid transporter that binds trehalose monomycolate and
RT phosphatidylethanolamine.";
RL Proc. Natl. Acad. Sci. U.S.A. 116:11241-11246(2019).
RN [10] {ECO:0007744|PDB:7C2M, ECO:0007744|PDB:7C2N}
RP X-RAY CRYSTALLOGRAPHY (2.82 ANGSTROMS) OF 1-748 IN COMPLEXES WITH
RP INHIBITORS NITD-349 AND SPIRO, ACTIVITY REGULATION, AND SITE.
RC STRAIN=ATCC 700084 / mc(2)155 {ECO:0000303|PubMed:32512002};
RX PubMed=32512002; DOI=10.1016/j.jmb.2020.05.019;
RA Yang X., Hu T., Yang X., Xu W., Yang H., Guddat L.W., Zhang B., Rao Z.;
RT "Structural Basis for the Inhibition of Mycobacterial MmpL3 by NITD-349 and
RT SPIRO.";
RL J. Mol. Biol. 432:4426-4434(2020).
CC -!- FUNCTION: Transports trehalose monomycolate (TMM) to the cell wall
CC (PubMed:31239378, PubMed:22520756, PubMed:28698380). Flips TMM across
CC the inner membrane. Membrane potential is not required for this
CC function (PubMed:28698380). Transports probably
CC phosphatidylethanolamine (PE) as well. Binds specifically both TMM and
CC PE, but not trehalose dimycolate (TDM). Binds also diacylglycerol (DAG)
CC and other phospholipids, including phosphatidylglycerol (PG),
CC phosphatidylinositol (PI), and cardiolipin (CDL) (PubMed:31113875).
CC Contributes to membrane potential, cell wall composition, antibiotic
CC susceptibility and fitness (PubMed:28703701).
CC {ECO:0000269|PubMed:22520756, ECO:0000269|PubMed:28698380,
CC ECO:0000269|PubMed:28703701, ECO:0000269|PubMed:31113875,
CC ECO:0000269|PubMed:31239378}.
CC -!- ACTIVITY REGULATION: Inhibited by the antimycobacterial compound BM212,
CC a pyrrole derivative (PubMed:28698380). Inhibited by the antitubercular
CC drug SQ109. Inhibited by the adamantyl urea derivative AU1235, the
CC indole carboxamide ICA38 and rimonabant, the antagonist for the
CC cannabinoid receptor CB1. The dissociation constant (Kd) values for
CC SQ109, AU1235, ICA38 and rimonabant are 1.65 uM, 0.29, 0.16 and 29.5,
CC respectively (PubMed:30682372). Inhibitory effects are due to binding
CC of the inhibitors at the proton-transportation channel most likely
CC dissipating the transmembrane electrochemical proton gradient needed
CC for substrate translocation (PubMed:30682372 PubMed:32512002).
CC {ECO:0000269|PubMed:28698380, ECO:0000269|PubMed:30682372,
CC ECO:0000305|PubMed:32512002}.
CC -!- SUBUNIT: Monomer (PubMed:30682372, PubMed:31113875). Interacts with
CC TtfA (via N-terminus); active trehalose monomycolate (TMM) biosynthesis
CC is not required for the complex formation. Interacts with MSMEG_5308
CC (PubMed:31239378). {ECO:0000269|PubMed:30682372,
CC ECO:0000269|PubMed:31113875, ECO:0000269|PubMed:31239378}.
CC -!- SUBCELLULAR LOCATION: Cell inner membrane {ECO:0000269|PubMed:28698380,
CC ECO:0000269|PubMed:30682372, ECO:0000269|PubMed:31113875}; Multi-pass
CC membrane protein {ECO:0000255, ECO:0000305|PubMed:30682372,
CC ECO:0000305|PubMed:31113875}. Cell septum
CC {ECO:0000269|PubMed:31239378}. Cell tip {ECO:0000269|PubMed:31239378}.
CC Note=Colocalizes with TtfA to the cell poles and septa. Trehalose
CC monomycolate (TMM) synthesis is not required for localization to the
CC poles or septa. {ECO:0000269|PubMed:31239378}.
CC -!- DISRUPTION PHENOTYPE: Cells lacking this gene are not viable
CC (PubMed:22520756). Knockdown or depletion of this gene leads to
CC accummulation of trehalose monomycolate (TMM) and lack of trehalose
CC dimycolate (TDM) (PubMed:31239378, PubMed:22520756). Decrease in
CC mycolylation of arabinogalactan (AG) (PubMed:22520756). Accumulates
CC MSMEG_5308 protein (PubMed:31239378). {ECO:0000269|PubMed:22520756,
CC ECO:0000269|PubMed:31239378}.
CC -!- BIOTECHNOLOGY: This protein is a target of small molecules which can be
CC validated by developed assays that measure the topology of trehalose
CC monomycolate (TMM) in the inner membrane of mycobacterial spheroplasts
CC after which they may be developed to future antituberculosis drugs
CC (PubMed:28698380). Designing improved inhibitors against this protein
CC could be achieved by avoiding direct contacts with the identified
CC residues that can mutate to confer drug resistance. Alternatively,
CC incorporating conformational flexibility in the inhibitors can allow
CC them to adapt to structural changes in the inhibitor binding pocket due
CC to mutation (PubMed:30682372). {ECO:0000269|PubMed:28698380,
CC ECO:0000269|PubMed:30682372}.
CC -!- MISCELLANEOUS: Binds antitubercular compounds N-(4,4-
CC dimethylcyclohexyl)-4,6-difluoro-1H-indole-2-carboxamide (NITD-349) and
CC 1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl) methyl)-6',7'-
CC dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] (SPIRO) with Kd values
CC of 0.05 uM and 0.8 uM, respectively. {ECO:0000269|PubMed:32512002}.
CC -!- SIMILARITY: Belongs to the resistance-nodulation-cell division (RND)
CC (TC 2.A.6) family. MmpL subfamily. {ECO:0000305}.
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DR EMBL; CP000480; ABK74656.1; -; Genomic_DNA.
DR EMBL; CP001663; AFP36724.1; -; Genomic_DNA.
DR RefSeq; WP_011726778.1; NZ_CP009494.1.
DR RefSeq; YP_884665.1; NC_008596.1.
DR PDB; 6AJF; X-ray; 2.70 A; A=1-748.
DR PDB; 6AJG; X-ray; 2.60 A; A=1-748.
DR PDB; 6AJH; X-ray; 2.82 A; A=1-748.
DR PDB; 6AJI; X-ray; 2.90 A; A=1-748.
DR PDB; 6AJJ; X-ray; 2.79 A; A=1-748.
DR PDB; 6N40; X-ray; 3.31 A; A=1-773.
DR PDB; 6OR2; X-ray; 2.59 A; A=1-773.
DR PDB; 7C2M; X-ray; 3.10 A; A=1-748.
DR PDB; 7C2N; X-ray; 2.82 A; A=1-748.
DR PDB; 7K7M; X-ray; 3.33 A; A/B=1-780.
DR PDB; 7K8A; EM; 3.65 A; A=1-1013.
DR PDB; 7K8B; EM; 2.94 A; A=1-1013.
DR PDB; 7K8C; EM; 4.27 A; A=1-1013.
DR PDB; 7K8D; EM; 4.33 A; A=1-1013.
DR PDB; 7N6B; EM; 2.66 A; A=1-1013.
DR PDBsum; 6AJF; -.
DR PDBsum; 6AJG; -.
DR PDBsum; 6AJH; -.
DR PDBsum; 6AJI; -.
DR PDBsum; 6AJJ; -.
DR PDBsum; 6N40; -.
DR PDBsum; 6OR2; -.
DR PDBsum; 7C2M; -.
DR PDBsum; 7C2N; -.
DR PDBsum; 7K7M; -.
DR PDBsum; 7K8A; -.
DR PDBsum; 7K8B; -.
DR PDBsum; 7K8C; -.
DR PDBsum; 7K8D; -.
DR PDBsum; 7N6B; -.
DR AlphaFoldDB; A0QP27; -.
DR SMR; A0QP27; -.
DR STRING; 246196.MSMEI_0243; -.
DR PRIDE; A0QP27; -.
DR EnsemblBacteria; ABK74656; ABK74656; MSMEG_0250.
DR EnsemblBacteria; AFP36724; AFP36724; MSMEI_0243.
DR GeneID; 66738438; -.
DR KEGG; msg:MSMEI_0243; -.
DR KEGG; msm:MSMEG_0250; -.
DR PATRIC; fig|246196.19.peg.246; -.
DR eggNOG; COG2409; Bacteria.
DR OMA; SRAYLNW; -.
DR OrthoDB; 149255at2; -.
DR Proteomes; UP000000757; Chromosome.
DR Proteomes; UP000006158; Chromosome.
DR GO; GO:0060187; C:cell pole; IDA:UniProtKB.
DR GO; GO:0030428; C:cell septum; IDA:UniProtKB.
DR GO; GO:0051286; C:cell tip; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:1901612; F:cardiolipin binding; IDA:UniProtKB.
DR GO; GO:0019992; F:diacylglycerol binding; IDA:UniProtKB.
DR GO; GO:0008429; F:phosphatidylethanolamine binding; IDA:UniProtKB.
DR GO; GO:1904121; F:phosphatidylethanolamine transfer activity; IC:UniProtKB.
DR GO; GO:1901611; F:phosphatidylglycerol binding; IDA:UniProtKB.
DR GO; GO:0035091; F:phosphatidylinositol binding; IDA:UniProtKB.
DR GO; GO:0015574; F:trehalose transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0042546; P:cell wall biogenesis; IDA:UniProtKB.
DR GO; GO:0071555; P:cell wall organization; IEA:UniProtKB-KW.
DR GO; GO:0071769; P:mycolate cell wall layer assembly; IDA:UniProtKB.
DR GO; GO:0071768; P:mycolic acid biosynthetic process; IDA:UniProtKB.
DR GO; GO:0015914; P:phospholipid transport; IC:UniProtKB.
DR GO; GO:0042391; P:regulation of membrane potential; IDA:UniProtKB.
DR GO; GO:0046677; P:response to antibiotic; IMP:UniProtKB.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IDA:UniProtKB.
DR GO; GO:0015771; P:trehalose transport; IDA:UniProtKB.
DR InterPro; IPR004869; MMPL_dom.
DR Pfam; PF03176; MMPL; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Cell inner membrane; Cell membrane;
KW Cell wall biogenesis/degradation; Lipid transport; Membrane;
KW Reference proteome; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..1013
FT /note="Trehalose monomycolate exporter MmpL3"
FT /id="PRO_0000452686"
FT TOPO_DOM 1..14
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:30682372,
FT ECO:0000305|PubMed:31113875"
FT TRANSMEM 15..35
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 36..196
FT /note="Periplasmic"
FT /evidence="ECO:0000305|PubMed:30682372,
FT ECO:0000305|PubMed:31113875"
FT TRANSMEM 197..217
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 218..238
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 239..240
FT /note="Periplasmic"
FT /evidence="ECO:0000305|PubMed:30682372,
FT ECO:0000305|PubMed:31113875"
FT TRANSMEM 241..261
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 262..290
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:30682372,
FT ECO:0000305|PubMed:31113875"
FT TRANSMEM 291..311
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 312..317
FT /note="Periplasmic"
FT /evidence="ECO:0000305|PubMed:30682372,
FT ECO:0000305|PubMed:31113875"
FT TRANSMEM 318..338
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 339..401
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:30682372,
FT ECO:0000305|PubMed:31113875"
FT TRANSMEM 402..422
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 423..567
FT /note="Periplasmic"
FT /evidence="ECO:0000305|PubMed:30682372,
FT ECO:0000305|PubMed:31113875"
FT TRANSMEM 568..588
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 589..591
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:30682372,
FT ECO:0000305|PubMed:31113875"
FT TRANSMEM 592..612
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 613..630
FT /note="Periplasmic"
FT /evidence="ECO:0000305|PubMed:30682372,
FT ECO:0000305|PubMed:31113875"
FT TRANSMEM 631..651
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 652..678
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:30682372,
FT ECO:0000305|PubMed:31113875"
FT TRANSMEM 679..699
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 700..703
FT /note="Periplasmic"
FT /evidence="ECO:0000305|PubMed:30682372,
FT ECO:0000305|PubMed:31113875"
FT TRANSMEM 704..724
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 725..1013
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:30682372,
FT ECO:0000305|PubMed:31113875"
FT REGION 485..513
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 754..1013
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 492..507
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 754..769
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 778..804
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 978..998
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 40..44
FT /ligand="1,2-diacylglycero-3-phosphoethanolamine"
FT /ligand_id="ChEBI:CHEBI:57613"
FT /evidence="ECO:0000269|PubMed:31113875,
FT ECO:0007744|PDB:6OR2"
FT BINDING 645
FT /ligand="SQ109"
FT /ligand_id="ChEBI:CHEBI:188155"
FT /ligand_note="inhibitor; antitubercular drug"
FT /evidence="ECO:0000269|PubMed:30682372,
FT ECO:0007744|PDB:6AJG"
FT SITE 256
FT /note="Part of the proton-transportation channel"
FT /evidence="ECO:0000305|PubMed:30682372,
FT ECO:0000305|PubMed:31113875"
FT SITE 257
FT /note="Part of the proton-transportation channel"
FT /evidence="ECO:0000305|PubMed:30682372,
FT ECO:0000305|PubMed:31113875"
FT SITE 591
FT /note="Part of the proton transportation network"
FT /evidence="ECO:0000305|PubMed:31113875"
FT SITE 645
FT /note="Part of the proton-transportation channel"
FT /evidence="ECO:0000305|PubMed:30682372,
FT ECO:0000305|PubMed:31113875, ECO:0000305|PubMed:32512002"
FT SITE 646
FT /note="Part of the proton-transportation channel"
FT /evidence="ECO:0000305|PubMed:30682372,
FT ECO:0000305|PubMed:31113875"
FT SITE 647
FT /note="Part of the proton transportation network"
FT /evidence="ECO:0000305|PubMed:31113875"
FT VARIANT 197
FT /note="V -> M (increases resistance to BM212 with 4-fold
FT increase in minimal inhibitory concentration (MIC) to BM212
FT in liquid and solid media)"
FT /evidence="ECO:0000269|PubMed:28698380"
FT VARIANT 257
FT /note="Y -> C (growth defect in both liquid and solid
FT media; confers resistance to SQ109 and AU1235 with 2-fold
FT and 4-fold increased resistance, respectively; disrupted
FT membrane potential; increased cell wall hydrophobicity;
FT more sensitive to ampicillin and the hydrophobic
FT antibiotics, rifampicin and erythromycin, but no change in
FT sensitivity to chloramphenicol or kanamycin, compared to
FT wild-type)"
FT /evidence="ECO:0000269|PubMed:28703701,
FT ECO:0000269|PubMed:30682372"
FT VARIANT 293
FT /note="S -> A (growth defect in both liquid and solid
FT media; confers resistance to SQ109 and AU1235 with 4-fold
FT and 33-fold increased resistance, respectively; disrupted
FT membrane potential; no significant difference in cell wall
FT hydrophobicity; more sensitive to ampicillin and the
FT hydrophobic antibiotics, rifampicin and erythromycin, but
FT no change in sensitivity to chloramphenicol or kanamycin,
FT compared to wild-type)"
FT /evidence="ECO:0000269|PubMed:28703701,
FT ECO:0000269|PubMed:30682372"
FT VARIANT 293
FT /note="S -> T (grows as wild-type in liquid media; weak
FT binding to both SQ109 and ICA38 while the dissociation
FT constant (Kd) value for AU1235 increases 6.6-fold compared
FT with wild-type; 8-fold and 4-fold increased resistance to
FT AU1235 and SQ109, respectively; disrupted membrane
FT potential; increased cell wall hydrophobicity; more
FT sensitive to ampicillin and the hydrophobic antibiotics,
FT rifampicin and erythromycin, but no change in sensitivity
FT to chloramphenicol or kanamycin, compared to wild-type)"
FT /evidence="ECO:0000269|PubMed:28703701,
FT ECO:0000269|PubMed:30682372"
FT VARIANT 297
FT /note="I -> F (growth defect in certain liquid medium;
FT severely reduced binding to SQ109 and AU1235; no change in
FT resistance and 4-fold increased resistance to SQ109 and
FT AU1235, respectively; disrupted membrane potential;
FT increased cell wall hydrophobicity; more sensitive to
FT ampicillin and the hydrophobic antibiotics, rifampicin and
FT erythromycin, but no change in sensitivity to
FT chloramphenicol or kanamycin, compared to wild-type)"
FT /evidence="ECO:0000269|PubMed:28703701,
FT ECO:0000269|PubMed:30682372"
FT VARIANT 326
FT /note="A -> T (increases resistance to BM212 with 4-fold
FT increase in minimal inhibitory concentration (MIC) to BM212
FT in liquid and solid media)"
FT /evidence="ECO:0000269|PubMed:28698380"
FT VARIANT 750
FT /note="G -> D (rescues the growth defect of A-293 variant
FT by partially restoring the membrane potential)"
FT /evidence="ECO:0000269|PubMed:28703701"
FT MUTAGEN 40
FT /note="Q->R: Binds to SQ109 with a dissociation constant
FT (Kd) value similar to wild-type."
FT /evidence="ECO:0000269|PubMed:30682372"
FT MUTAGEN 194
FT /note="I->R: Binds to ICA38 with a dissociation constant
FT (Kd) value similar to wild-type."
FT /evidence="ECO:0000269|PubMed:30682372"
FT MUTAGEN 301
FT /note="S->A: Binds to SQ109, AU1235, ICA38 and rimonabant
FT with a dissociation constant (Kd) values similar to wild-
FT type; when associated with T-319; L-638 and V-686."
FT /evidence="ECO:0000269|PubMed:30682372"
FT MUTAGEN 316
FT /note="T->I: Confers resistance to ICA38."
FT /evidence="ECO:0000269|PubMed:30682372"
FT MUTAGEN 319
FT /note="I->T: Binds to SQ109, AU1235, ICA38 and rimonabant
FT with a dissociation constant (Kd) values similar to wild-
FT type; when associated with A-301; L-638 and V-686."
FT /evidence="ECO:0000269|PubMed:30682372"
FT MUTAGEN 572
FT /note="I->P: Binds to SQ109 with a dissociation constant
FT (Kd) value similar to wild-type."
FT /evidence="ECO:0000269|PubMed:30682372"
FT MUTAGEN 596
FT /note="S->I: Confers resistance to ICA38."
FT /evidence="ECO:0000269|PubMed:30682372"
FT MUTAGEN 638
FT /note="V->L: Binds to SQ109, AU1235, ICA38 and rimonabant
FT with a dissociation constant (Kd) value similar to wild-
FT type; when associated with A-301; T-319 and V-686."
FT /evidence="ECO:0000269|PubMed:30682372"
FT MUTAGEN 686
FT /note="L->V: Binds to SQ109, AU1235, ICA38 and rimonabant
FT with a dissociation constant (Kd) value similar to wild-
FT type; when associated with A-301; T-319 and L-638."
FT /evidence="ECO:0000269|PubMed:30682372"
FT MUTAGEN 688
FT /note="V->G: Binds to ICA38 with a dissociation constant
FT (Kd) value similar to wild-type."
FT /evidence="ECO:0000269|PubMed:30682372"
FT MUTAGEN 689
FT /note="V->G: Binds to ICA38 with a dissociation constant
FT (Kd) value similar to wild-type."
FT /evidence="ECO:0000269|PubMed:30682372"
FT MUTAGEN 705
FT /note="A->T: Binds to SQ109 with a dissociation constant
FT (Kd) value similar to wild-type."
FT /evidence="ECO:0000269|PubMed:30682372"
FT HELIX 2..11
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 13..31
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 32..36
FT /evidence="ECO:0007829|PDB:6OR2"
FT STRAND 37..40
FT /evidence="ECO:0007829|PDB:6AJG"
FT STRAND 46..48
FT /evidence="ECO:0007829|PDB:7K7M"
FT HELIX 49..61
FT /evidence="ECO:0007829|PDB:6OR2"
FT STRAND 70..73
FT /evidence="ECO:0007829|PDB:6OR2"
FT STRAND 76..78
FT /evidence="ECO:0007829|PDB:7N6B"
FT HELIX 84..100
FT /evidence="ECO:0007829|PDB:6OR2"
FT TURN 101..104
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 111..113
FT /evidence="ECO:0007829|PDB:6OR2"
FT STRAND 114..116
FT /evidence="ECO:0007829|PDB:7N6B"
FT HELIX 120..123
FT /evidence="ECO:0007829|PDB:6OR2"
FT STRAND 128..131
FT /evidence="ECO:0007829|PDB:7K7M"
FT STRAND 133..136
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 144..159
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 162..164
FT /evidence="ECO:0007829|PDB:6OR2"
FT STRAND 166..170
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 171..191
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 193..205
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 208..232
FT /evidence="ECO:0007829|PDB:6OR2"
FT TURN 233..235
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 242..248
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 250..271
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 275..301
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 302..306
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 310..330
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 333..341
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 342..346
FT /evidence="ECO:0007829|PDB:6OR2"
FT STRAND 347..349
FT /evidence="ECO:0007829|PDB:6AJG"
FT TURN 350..353
FT /evidence="ECO:0007829|PDB:6AJG"
FT TURN 357..360
FT /evidence="ECO:0007829|PDB:7K7M"
FT HELIX 365..376
FT /evidence="ECO:0007829|PDB:7N6B"
FT HELIX 383..399
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 402..414
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 415..421
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 429..431
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 437..448
FT /evidence="ECO:0007829|PDB:6OR2"
FT STRAND 450..453
FT /evidence="ECO:0007829|PDB:7K8B"
FT STRAND 456..463
FT /evidence="ECO:0007829|PDB:6OR2"
FT STRAND 464..467
FT /evidence="ECO:0007829|PDB:7K8B"
FT HELIX 471..481
FT /evidence="ECO:0007829|PDB:6OR2"
FT STRAND 490..492
FT /evidence="ECO:0007829|PDB:7C2M"
FT HELIX 494..496
FT /evidence="ECO:0007829|PDB:6OR2"
FT STRAND 497..500
FT /evidence="ECO:0007829|PDB:6OR2"
FT STRAND 505..507
FT /evidence="ECO:0007829|PDB:7N6B"
FT STRAND 513..521
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 523..525
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 526..534
FT /evidence="ECO:0007829|PDB:6OR2"
FT STRAND 542..548
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 549..582
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 587..611
FT /evidence="ECO:0007829|PDB:6OR2"
FT TURN 612..616
FT /evidence="ECO:0007829|PDB:7K8B"
FT HELIX 617..620
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 629..658
FT /evidence="ECO:0007829|PDB:6OR2"
FT TURN 659..661
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 664..674
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 676..693
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 699..716
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 718..721
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 723..731
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 732..736
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 740..749
FT /evidence="ECO:0007829|PDB:6OR2"
FT HELIX 751..759
FT /evidence="ECO:0007829|PDB:7C2N"
FT STRAND 762..767
FT /evidence="ECO:0007829|PDB:7C2N"
FT STRAND 774..777
FT /evidence="ECO:0007829|PDB:7C2N"
SQ SEQUENCE 1013 AA; 109399 MW; 2C0B090D822541E4 CRC64;
MFAWWGRTVY QFRYIVIGVM VALCLGGGVY GISLGNHVTQ SGFYDEGSQS VAASLIGDEV
YGRDRTSHVV AILTPPDDKK VTDKAWQKKV TEELDQVVKD HEDQIVGWVG WLKAPDTTDP
TVSAMKTQDL RHTFISIPLQ GDDDDEILKN YQVVEPELQQ VNGGDIRLAG LNPLASELTG
TIGEDQKRAE VAAIPLVAVV LFFVFGTVIA AALPAIIGGL AIAGALGIMR LVAEFTPVHF
FAQPVVTLIG LGIAIDYGLF IVSRFREEIA EGYDTEAAVR RTVMTSGRTV VFSAVIIVAS
SVPLLLFPQG FLKSITYAII ASVMLAAILS ITVLAAALAI LGPRVDALGV TTLLKIPFLA
NWQFSRRIID WFAEKTQKTK TREEVERGFW GRLVNVVMKR PIAFAAPILV VMVLLIIPLG
QLSLGGISEK YLPPDNAVRQ SQEQFDKLFP GFRTEPLTLV MKREDGEPIT DAQIADMRAK
ALTVSGFTDP DNDPEKMWKE RPANDSGSKD PSVRVIQNGL ENRNDAAKKI DELRALQPPH
GIEVFVGGTP ALEQDSIHSL FDKLPLMALI LIVTTTVLMF LAFGSVVLPI KAALMSALTL
GSTMGILTWM FVDGHGSGLM NYTPQPLMAP MIGLIIAVIW GLSTDYEVFL VSRMVEARER
GMSTAEAIRI GTATTGRLIT GAALILAVVA GAFVFSDLVM MKYLAFGLLI ALLLDATIIR
MFLVPAVMKL LGDDCWWAPR WMKRVQEKLG LGETELPDER KRPTVRESET DQRALVGVGA
PPPPPRPHDP THPAPEPVRP MPPMRSNAPS AAGTARISTP PQPPQPPQAP AQQAGDEPAT
TRFAMARNAV RNAVNSAVHG GAGSAAAPTE RAPRPGGPAQ PPAPPQREER EIESWLGALR
GPAPAKNVPQ PPAQPQRPST DTTRAMPPQG RPPAGPADRG NENAPTTAFS AQRPPNGGAP
ADATTAIPTP PQREQEPSTE KLNTREDAPE DPETKRRGGG MSAQDLLRRE GRL
