MDR1_CRYNH
ID MDR1_CRYNH Reviewed; 1408 AA.
AC J9VF33;
DT 02-JUN-2021, integrated into UniProtKB/Swiss-Prot.
DT 28-NOV-2012, sequence version 1.
DT 03-AUG-2022, entry version 57.
DE RecName: Full=ABC multidrug transporter MDR1 {ECO:0000303|PubMed:25630649};
GN Name=MDR1 {ECO:0000303|PubMed:25630649}; ORFNames=CNAG_00796;
OS Cryptococcus neoformans var. grubii serotype A (strain H99 / ATCC 208821 /
OS CBS 10515 / FGSC 9487) (Filobasidiella neoformans var. grubii).
OC Eukaryota; Fungi; Dikarya; Basidiomycota; Agaricomycotina; Tremellomycetes;
OC Tremellales; Cryptococcaceae; Cryptococcus;
OC Cryptococcus neoformans species complex.
OX NCBI_TaxID=235443;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=H99 / ATCC 208821 / CBS 10515 / FGSC 9487;
RX PubMed=24743168; DOI=10.1371/journal.pgen.1004261;
RA Janbon G., Ormerod K.L., Paulet D., Byrnes E.J. III, Yadav V.,
RA Chatterjee G., Mullapudi N., Hon C.-C., Billmyre R.B., Brunel F.,
RA Bahn Y.-S., Chen W., Chen Y., Chow E.W.L., Coppee J.-Y., Floyd-Averette A.,
RA Gaillardin C., Gerik K.J., Goldberg J., Gonzalez-Hilarion S., Gujja S.,
RA Hamlin J.L., Hsueh Y.-P., Ianiri G., Jones S., Kodira C.D., Kozubowski L.,
RA Lam W., Marra M., Mesner L.D., Mieczkowski P.A., Moyrand F., Nielsen K.,
RA Proux C., Rossignol T., Schein J.E., Sun S., Wollschlaeger C., Wood I.A.,
RA Zeng Q., Neuveglise C., Newlon C.S., Perfect J.R., Lodge J.K., Idnurm A.,
RA Stajich J.E., Kronstad J.W., Sanyal K., Heitman J., Fraser J.A.,
RA Cuomo C.A., Dietrich F.S.;
RT "Analysis of the genome and transcriptome of Cryptococcus neoformans var.
RT grubii reveals complex RNA expression and microevolution leading to
RT virulence attenuation.";
RL PLoS Genet. 10:E1004261-E1004261(2014).
RN [2]
RP FUNCTION, CATALYTIC ACTIVITY, SUBSTRATE SPECIFICITY, BIOPHYSICOCHEMICAL
RP PROPERTIES, AND SUBCELLULAR LOCATION.
RX PubMed=25630649; DOI=10.1093/jac/dku554;
RA Basso L.R. Jr., Gast C.E., Bruzual I., Wong B.;
RT "Identification and properties of plasma membrane azole efflux pumps from
RT the pathogenic fungi Cryptococcus gattii and Cryptococcus neoformans.";
RL J. Antimicrob. Chemother. 70:1396-1407(2015).
RN [3]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=29378705; DOI=10.1128/aac.01751-17;
RA Chang M., Sionov E., Khanal Lamichhane A., Kwon-Chung K.J., Chang Y.C.;
RT "Roles of three Cryptococcus neoformans and Cryptococcus gattii efflux
RT pump-coding genes in response to drug treatment.";
RL Antimicrob. Agents Chemother. 62:0-0(2018).
CC -!- FUNCTION: Pleiotropic ABC efflux transporter that confers resistance to
CC structurally and functionally unrelated compounds including azoles such
CC as fluconazole (FLC), itraconazole (ITC), posaconazole (POS), and
CC voriconazole (VRC). {ECO:0000269|PubMed:25630649,
CC ECO:0000269|PubMed:29378705}.
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:25630649};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:33504;
CC Evidence={ECO:0000269|PubMed:25630649};
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:25630649};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:61913;
CC Evidence={ECO:0000269|PubMed:25630649};
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:25630649};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:61917;
CC Evidence={ECO:0000269|PubMed:25630649};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.11 uM for fluconazole transport {ECO:0000269|PubMed:25630649};
CC Vmax=1.46 pmol/min/mg enzyme for fluconazole transport
CC {ECO:0000269|PubMed:25630649};
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:25630649};
CC Multi-pass membrane protein {ECO:0000255}.
CC -!- DISRUPTION PHENOTYPE: Causes higher susceptibility to itraconazole
CC (ITC) and rhodamine 6G (R-6G) (PubMed:29378705). Causes further
CC increase in susceptibility toward fluconazole and itraconazole, when
CC AFR1 and MDR1 are also deleted (PubMed:29378705).
CC {ECO:0000269|PubMed:29378705}.
CC -!- SIMILARITY: Belongs to the ABC transporter superfamily. ABCB family.
CC Multidrug resistance exporter (TC 3.A.1.201) subfamily. {ECO:0000305}.
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DR EMBL; CP003820; AFR92927.1; -; Genomic_DNA.
DR RefSeq; XP_012046966.1; XM_012191576.1.
DR AlphaFoldDB; J9VF33; -.
DR SMR; J9VF33; -.
DR EnsemblFungi; AFR92927; AFR92927; CNAG_00796.
DR GeneID; 23884573; -.
DR VEuPathDB; FungiDB:CNAG_00796; -.
DR HOGENOM; CLU_000604_17_2_1; -.
DR Proteomes; UP000010091; Chromosome 1.
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:0140359; F:ABC-type transporter activity; IEA:InterPro.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR Gene3D; 1.20.1560.10; -; 1.
DR Gene3D; 3.40.50.300; -; 2.
DR InterPro; IPR003593; AAA+_ATPase.
DR InterPro; IPR011527; ABC1_TM_dom.
DR InterPro; IPR036640; ABC1_TM_sf.
DR InterPro; IPR003439; ABC_transporter-like_ATP-bd.
DR InterPro; IPR017871; ABC_transporter-like_CS.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR039421; Type_1_exporter.
DR PANTHER; PTHR24221; PTHR24221; 1.
DR Pfam; PF00664; ABC_membrane; 2.
DR Pfam; PF00005; ABC_tran; 2.
DR SMART; SM00382; AAA; 2.
DR SUPFAM; SSF52540; SSF52540; 2.
DR SUPFAM; SSF90123; SSF90123; 2.
DR PROSITE; PS50929; ABC_TM1F; 2.
DR PROSITE; PS00211; ABC_TRANSPORTER_1; 2.
DR PROSITE; PS50893; ABC_TRANSPORTER_2; 2.
PE 1: Evidence at protein level;
KW ATP-binding; Cell membrane; Glycoprotein; Membrane; Nucleotide-binding;
KW Repeat; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1..1408
FT /note="ABC multidrug transporter MDR1"
FT /id="PRO_0000452667"
FT TRANSMEM 147..167
FT /note="Helical"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00441"
FT TRANSMEM 223..243
FT /note="Helical"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00441"
FT TRANSMEM 296..316
FT /note="Helical"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00441"
FT TRANSMEM 321..341
FT /note="Helical"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00441"
FT TRANSMEM 408..428
FT /note="Helical"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00441"
FT TRANSMEM 436..456
FT /note="Helical"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00441"
FT TRANSMEM 838..858
FT /note="Helical"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00441"
FT TRANSMEM 882..902
FT /note="Helical"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00441"
FT TRANSMEM 952..972
FT /note="Helical"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00441"
FT TRANSMEM 981..999
FT /note="Helical"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00441"
FT TRANSMEM 1072..1092
FT /note="Helical"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00441"
FT TRANSMEM 1099..1119
FT /note="Helical"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00441"
FT DOMAIN 157..464
FT /note="ABC transmembrane type-1 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT DOMAIN 499..744
FT /note="ABC transporter 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT DOMAIN 838..1125
FT /note="ABC transmembrane type-1 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00441"
FT DOMAIN 1162..1402
FT /note="ABC transporter 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT REGION 79..102
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 79..96
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 534..541
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT BINDING 1197..1204
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00434"
FT CARBOHYD 244
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 606
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 934
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 1127
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 1182
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 1404
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 1408 AA; 152145 MW; CE8A34A09A6F69F8 CRC64;
MSASPGLTAA AAGPDHLQAR RDEKVIDSEK DALAHDAHAV NSGIPYPTAT APNVGAPTVP
ISVGRVSSAA EGKISRSSIA ASSDTLRNSP LEKPISNAFS KSHPYKKSKF DFLKSRKKKE
EEERKNKEKE KEASVLPPVS FFALFRFAAP LEIIAMVLGL VLAVAAGSCQ PLMTLIFGRL
TTSFTNYAVI ANQISQGGLT PETSAALQAA KDDLKTQSGH NALYLMAIGI GMFLATWLYM
FIWNVTGELN SKRIRERYLA AVLRQEIAYF DDLGAGEVAT RIQTDCHLVQ EGTSEKVALV
FQYAGTFVCG FVLAFVRSPR LAGALVSILP VIMLCGGIMM TAMAKYGTAA LDHIAKAGSL
AEEVIGSIRT VQAFGKEKIL GDKFADHIEQ SKIVGRKGSI FEGFGLSIMF FVIYAAYALA
FFYGGILVSN GQADSGIVIN VFMSILIGSF SMAMLAPELA AVTKARGAAA KLFATIDRVP
AIDSASEEGF KPDGLRGEIS FENVKFHYPS RPSIPILKGF TTTFEAGKTF ALVGASGSGK
STVVSLIERF YDPVSGVVKL DGRDIRSLNL NWLRQQIGLV SQEPTLFGTT VRGNVEHGLI
GSRYENASLE EKFELVKKAC VDANAHNFIM KLPQGYDTMV GERGMLLSGG QKQRVAIARA
IVSDPRILLL DEATSALDTQ SEGIVQDALD KASRGRTTIT IAHRLSTIRD ADRIYVMGGG
EVLEQGSHND LLANENGPYA QLVNNQKLAQ EAAAEALQVD DDIEDPDDAV FIGGSSPMQE
KDKQLHRAVT GRSLASIAMD DIQAKRAEEV AGEDKIPSSF GLYARLLRMN SADKFIYIIA
FIAAICAGMV YPSLAILFGK ALSDFEIQDP AELRHALSRS ALWYFITALA AAFVIFFQSA
GFSRAGWDLN GVLRKKLFTA TLRHDIEWFD EERNSTGAVT SNLADQPQKV QGLFGPTLGT
VVQSCATLIG GCIIGLCYGP LLALIGIACI PILVSGGYIR LKVVVLKDQR MKKLHAASAH
LASEAAGAVK TVASLTREKD VRRIYSEALK APMKLNFRTS IKSQCLFAAS QGLTFCIIAL
VFYIGALWII DAKYSTASFY TVLNSIVFAS IQAGNVFTFV PDASKANSSA ASIFRSIDNE
PAINAESNEG KVLDHKHVVG HVRIEGVHFR YPTRPGVRVL RNLTIDVPAG TYVALVGPSG
CGKSTTIQML ERFYDPLAGR VTLDGIDIKE LNLASYRSQI SLVSQEPTLY AGTIRFNILL
GANKPIEEVT QDEIDAACKD ANIYDFIVSL PDGFDTEVGG KGSQLSGGQK QRIAIARALI
RNPKVLLLDE ATSALDSQSE KVVQEALDKA AKGRTTIAIA HRLSSIQHSD RIYYFSEGRV
AEHGTHQELL AKKGGYYELV QMQNLSRQ
