MDR3_TRIRC
ID MDR3_TRIRC Reviewed; 1503 AA.
AC F2SG60;
DT 13-NOV-2019, integrated into UniProtKB/Swiss-Prot.
DT 13-NOV-2019, sequence version 3.
DT 03-AUG-2022, entry version 54.
DE RecName: Full=ABC multidrug transporter MDR3 {ECO:0000303|PubMed:31501141};
DE AltName: Full=Multidrug resistance protein 3 {ECO:0000303|PubMed:31501141};
GN Name=MDR3 {ECO:0000303|PubMed:31501141}; ORFNames=TERG_02186;
OS Trichophyton rubrum (strain ATCC MYA-4607 / CBS 118892) (Athlete's foot
OS fungus).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Onygenales; Arthrodermataceae; Trichophyton.
OX NCBI_TaxID=559305;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC MYA-4607 / CBS 118892;
RX PubMed=22951933; DOI=10.1128/mbio.00259-12;
RA Martinez D.A., Oliver B.G., Graeser Y., Goldberg J.M., Li W.,
RA Martinez-Rossi N.M., Monod M., Shelest E., Barton R.C., Birch E.,
RA Brakhage A.A., Chen Z., Gurr S.J., Heiman D., Heitman J., Kosti I.,
RA Rossi A., Saif S., Samalova M., Saunders C.W., Shea T., Summerbell R.C.,
RA Xu J., Young S., Zeng Q., Birren B.W., Cuomo C.A., White T.C.;
RT "Comparative genome analysis of Trichophyton rubrum and related
RT dermatophytes reveals candidate genes involved in infection.";
RL MBio 3:E259-E259(2012).
RN [2]
RP IDENTIFICATION, GENE MODEL REVISION, FUNCTION, INDUCTION, CATALYTIC
RP ACTIVITY, ACTIVITY REGULATION, AND DISRUPTION PHENOTYPE.
RX PubMed=31501141; DOI=10.1128/aac.00863-19;
RA Monod M., Feuermann M., Salamin K., Fratti M., Makino M., Alshahni M.M.,
RA Makimura K., Yamada T.;
RT "Trichophyton rubrum azole resistance mediated by a new ABC transporter,
RT TruMDR3.";
RL Antimicrob. Agents Chemother. 0:0-0(2019).
RN [3]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=33896045; DOI=10.1111/myc.13286;
RA Yamada T., Yaguchi T., Tamura T., Pich C., Salamin K., Feuermann M.,
RA Monod M.;
RT "Itraconazole resistance of Trichophyton rubrum mediated by the ABC
RT transporter TruMDR2.";
RL Mycoses 64:936-946(2021).
CC -!- FUNCTION: Pleiotropic ABC efflux transporter involved in the modulation
CC susceptibility to azoles, including fluconazole, itraconazole,
CC ketoconazole, miconazole and voriconazole.
CC {ECO:0000269|PubMed:31501141, ECO:0000269|PubMed:33896045}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + H2O + itraconazole(in) = ADP + H(+) + itraconazole(out)
CC + phosphate; Xref=Rhea:RHEA:33503, ChEBI:CHEBI:6076,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000269|PubMed:31501141};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:33504;
CC Evidence={ECO:0000269|PubMed:31501141};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + H2O + voriconazole(in) = ADP + H(+) + phosphate +
CC voriconazole(out); Xref=Rhea:RHEA:61912, ChEBI:CHEBI:10023,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000269|PubMed:31501141};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:61913;
CC Evidence={ECO:0000269|PubMed:31501141};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + fluconazole(in) + H2O = ADP + fluconazole(out) + H(+) +
CC phosphate; Xref=Rhea:RHEA:61916, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:46081, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000269|PubMed:31501141};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:61917;
CC Evidence={ECO:0000269|PubMed:31501141};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(2R,4S)-ketoconazole(in) + ATP + H2O = (2R,4S)-
CC ketoconazole(out) + ADP + H(+) + phosphate; Xref=Rhea:RHEA:61920,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:48336, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000269|PubMed:31501141};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:61921;
CC Evidence={ECO:0000269|PubMed:31501141};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(2S,4R)-ketoconazole(in) + ATP + H2O = (2S,4R)-
CC ketoconazole(out) + ADP + H(+) + phosphate; Xref=Rhea:RHEA:61924,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:47518, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000269|PubMed:31501141};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:61925;
CC Evidence={ECO:0000269|PubMed:31501141};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(R)-miconazole(in) + ATP + H2O = (R)-miconazole(out) + ADP +
CC H(+) + phosphate; Xref=Rhea:RHEA:61928, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:82894, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000269|PubMed:31501141};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:61929;
CC Evidence={ECO:0000269|PubMed:31501141};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(S)-miconazole(in) + ATP + H2O = (S)-miconazole(out) + ADP +
CC H(+) + phosphate; Xref=Rhea:RHEA:61932, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:82897, ChEBI:CHEBI:456216;
CC Evidence={ECO:0000269|PubMed:31501141};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:61933;
CC Evidence={ECO:0000269|PubMed:31501141};
CC -!- ACTIVITY REGULATION: Azole transport activity is inhibited by
CC milbemycin oxime. {ECO:0000269|PubMed:31501141}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000305|PubMed:31501141};
CC Multi-pass membrane protein {ECO:0000255}.
CC -!- INDUCTION: Expression is highly induced upon exposure to voriconazole
CC and itraconazole (PubMed:31501141). Is highly over-expressed in strain
CC TIMM20092, an azole-resistant strain isolated in Switzerland
CC (PubMed:31501141). {ECO:0000269|PubMed:31501141}.
CC -!- DISRUPTION PHENOTYPE: Impairs the resistance to voriconazole and
CC decreases the resistance to itraconazole of the azole-resistant strain
CC TIMM20092. {ECO:0000269|PubMed:31501141, ECO:0000269|PubMed:33896045}.
CC -!- MISCELLANEOUS: Dermatophytes showing reduced sensitivity to antifungal
CC agents have emerged in several countries and, in particular, up-
CC regulation of MDR3 expression in some clinical isolates such as strain
CC TIMM20092 leads to increased resistance to voriconazole, and to a
CC lesser extend itraconazole, during clinical treatments.
CC {ECO:0000269|PubMed:31501141, ECO:0000269|PubMed:33896045}.
CC -!- SIMILARITY: Belongs to the ABC transporter superfamily. ABCG family.
CC PDR (TC 3.A.1.205) subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=EGD85916.2; Type=Erroneous gene model prediction; Evidence={ECO:0000269|PubMed:31501141};
CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Backlash - Issue 221 of
CC January 2020;
CC URL="https://web.expasy.org/spotlight/back_issues/221/";
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DR EMBL; GG700649; EGD85916.2; ALT_SEQ; Genomic_DNA.
DR RefSeq; XP_003237465.1; XM_003237417.1.
DR AlphaFoldDB; F2SG60; -.
DR SMR; F2SG60; -.
DR STRING; 5551.XP_003237465.1; -.
DR TCDB; 3.A.1.205.32; the atp-binding cassette (abc) superfamily.
DR EnsemblFungi; EGD85916; EGD85916; TERG_02186.
DR GeneID; 10378844; -.
DR eggNOG; KOG0065; Eukaryota.
DR HOGENOM; CLU_000604_35_0_1; -.
DR InParanoid; F2SG60; -.
DR Proteomes; UP000008864; Unassembled WGS sequence.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0140394; F:ABC-type azole transporter activity; IMP:PHI-base.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:1990961; P:xenobiotic detoxification by transmembrane export across the plasma membrane; IMP:PHI-base.
DR CDD; cd03233; ABCG_PDR_domain1; 1.
DR CDD; cd03232; ABCG_PDR_domain2; 1.
DR Gene3D; 3.40.50.300; -; 2.
DR InterPro; IPR003593; AAA+_ATPase.
DR InterPro; IPR013525; ABC_2_trans.
DR InterPro; IPR029481; ABC_trans_N.
DR InterPro; IPR003439; ABC_transporter-like_ATP-bd.
DR InterPro; IPR017871; ABC_transporter-like_CS.
DR InterPro; IPR043926; ABCG_dom.
DR InterPro; IPR034001; ABCG_PDR_1.
DR InterPro; IPR034003; ABCG_PDR_2.
DR InterPro; IPR005285; Drug-R_PDR/CDR.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR010929; PDR_CDR_ABC.
DR Pfam; PF01061; ABC2_membrane; 2.
DR Pfam; PF19055; ABC2_membrane_7; 1.
DR Pfam; PF00005; ABC_tran; 2.
DR Pfam; PF14510; ABC_trans_N; 1.
DR Pfam; PF06422; PDR_CDR; 1.
DR SMART; SM00382; AAA; 2.
DR SUPFAM; SSF52540; SSF52540; 2.
DR TIGRFAMs; TIGR00956; 3a01205; 1.
DR PROSITE; PS00211; ABC_TRANSPORTER_1; 1.
DR PROSITE; PS50893; ABC_TRANSPORTER_2; 2.
PE 1: Evidence at protein level;
KW ATP-binding; Cell membrane; Glycoprotein; Membrane; Nucleotide-binding;
KW Reference proteome; Repeat; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..1503
FT /note="ABC multidrug transporter MDR3"
FT /id="PRO_0000448444"
FT TRANSMEM 519..539
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 554..574
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 599..619
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 628..648
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 662..682
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 771..791
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 1186..1206
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 1222..1242
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 1259..1279
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 1310..1330
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 1346..1366
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 1458..1478
FT /note="Helical"
FT /evidence="ECO:0000255"
FT DOMAIN 153..408
FT /note="ABC transporter 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT DOMAIN 850..1093
FT /note="ABC transporter 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT REGION 1..46
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 816..838
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 12..27
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 28..46
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 886..893
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT CARBOHYD 8
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 332
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 463
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 729
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 1499
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 1503 AA; 169082 MW; 31D321907E6F9C96 CRC64;
MAPTEEANVT KPTGELRPDE KLNYEEDVKC SGSSSTTVGK TAYDTDDISQ SQAAELQDLA
RQLSRASRQG GLDVENEPQQ VINPFLDSES DPELNPDSKS FNVAKWLKTI LQITSRDPER
FPKRTAGVSF RNMNVHGYGT AADYQSDVGN LPLKAWSGIM SMLGLRKKVR IDILRDFEGL
VKSGEMLVVL GRPGSGCSTL LRTLSGETHG LYLDEGNDIQ YQGISWEQMH KNFRGEVIYQ
AETETHFPQM TVGDTLYFAA RARAPANRLP GVSREQYAIH MRSMVMSMLS LSHTINTQVG
NEYIRGVSGG ERKRISIAET TLSGSPLQCW DNSTRGLDSA NALEFVKSLR LSTKYSGTTA
IVAIYQAGQA IYDIFDKAVV LYEGHQIYFG NAVRAKEYFI EMGFDCPSRQ TTADFLTSVT
SPSERRVRPG YESRVPQTPA EFAQRWKESE DRRILMQEID EYNKTYPLHG EQLQKFQASR
LAEKSRSTSK SSPYTLSYPM EIKLCMWRGF QRLKGDMSMT LTSIIGNIAM SLIIASVFYN
QQETTDSFFS RGSLLFFAIL MNAFASSLEI LTLWHQRPIV EKHDKYALYH PSSEAISSIL
VDMPAKLAVA IVFNLIIYFM TNLRRTPGHF FIFFLFSFTT TLTMSNVFRS IAAVSRTLSQ
ALVPTSIFML ALVIYTGFTI PVRDMRPWFK WISYINPIQY AFESLMINEF HDREFKCAVY
IPSGPGYSNV SGTSKICAAK GAMAGKPTVS GDVFLRETYS YYASHMWRNY GIIVAFFLFF
LFVYITATEL VSAKPSKGEI LVFPKGKVPA FLKQSKKKQD PEAASTQEKQ PVETSGHDQT
AAIVKQTSVF HWESVCYDIK IKKESRRILD NVDGWVKPGT LTALMGVSGA GKTTLLDVLA
NRVTMGVVTG EMLVDGRLRD DSFQRKTGYV QQQDLHLEIS TVREALTFSA LLRQPNTTPY
EEKVAYVEEV IKMLGMEEYA NAVVGVLGEG LNVEQRKRLT IGVEIAAKPD LLLFFDEPTS
GLDSQTAWSI CTLMRKLADH GQAVLCTIHQ PSAMLMQEFD RLLFLASGGR TVYFGELGKH
MSTLIEYFES KGAPKCPPDA NPAEWMLEVI GAAPGSKTDI DWPAVWRDSA ERVEVRRHLA
ELKSELSQKP QTPRLTGYGE FAMPLWKQYL IVQHRMFQQY WRSPDYIYSK ACLAIVPTLF
IGFTFYKEQV SLQGIQNQMF AIFMFMILFP NLVQQMMPYF VIQRSLYEVR ERPSKTYSWI
AFMISSVVVE IPWNALLTVP AFFCWYYPIG FYKNAIPTDA VTERSGTMFL LILIFLMFSS
TFSSMVIAGI EQAETGGNIA QLCFSLTLVF CGVLVSPTAM PGFWIFMYRL SPFTYFVSAV
LSTGVGRTDI VCAANEILRL TPAAGQTCME YLGPYTKFAG GRILTPDATD MCEFCAVADT
DTFLKGVNII FDERWRNIGI LFGYIAFNMV GAIGLYWLLR VPKRKSGVKQ GQQPQKQANE
TKA
