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- EMDB-60910: The structure of Candida albicans Cdr1 in milbemycin oxime-inhibi... -

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Basic information

Entry
Database: EMDB / ID: EMD-60910
TitleThe structure of Candida albicans Cdr1 in milbemycin oxime-inhibited state
Map data
Sample
  • Complex: The Cryo-EM structure of Candida albicans Cdr1 in milbemycin oxime-inhibited state
    • Protein or peptide: Pleiotropic ABC efflux transporter of multiple drugs CDR1
  • Ligand: Pip2(20:4/18:0)
  • Ligand: milbemycin oxime
KeywordsABC transporters / Pleiotropic drug resistance / Membrane protein / TRANSPORT PROTEIN
Function / homology
Function and homology information


fluconazole transmembrane transporter activity / fluconazole transport / azole transmembrane transport / phosphatidylethanolamine floppase activity / azole transmembrane transporter activity / corticosterone binding / estradiol binding / aminophospholipid flippase activity / phosphatidylserine floppase activity / phosphatidylcholine floppase activity ...fluconazole transmembrane transporter activity / fluconazole transport / azole transmembrane transport / phosphatidylethanolamine floppase activity / azole transmembrane transporter activity / corticosterone binding / estradiol binding / aminophospholipid flippase activity / phosphatidylserine floppase activity / phosphatidylcholine floppase activity / xenobiotic detoxification by transmembrane export across the plasma membrane / phospholipid translocation / response to cycloheximide / xenobiotic transmembrane transporter activity / ABC-type transporter activity / ribonucleoside triphosphate phosphatase activity / extracellular vesicle / response to antibiotic / nucleotide binding / cell surface / ATP hydrolysis activity / ATP binding / membrane / plasma membrane
Similarity search - Function
Pleiotropic drug resistance protein PDR/CDR / CDR ABC transporter / ABC-transporter, N-terminal domain / ATP-binding cassette transporter, PDR-like subfamily G, domain 1 / ATP-binding cassette transporter, PDR-like subfamily G, domain 2 / CDR ABC transporter / ABC-transporter N-terminal / ABC-2 type transporter / ABC-2 type transporter / ABC transporter-like, conserved site ...Pleiotropic drug resistance protein PDR/CDR / CDR ABC transporter / ABC-transporter, N-terminal domain / ATP-binding cassette transporter, PDR-like subfamily G, domain 1 / ATP-binding cassette transporter, PDR-like subfamily G, domain 2 / CDR ABC transporter / ABC-transporter N-terminal / ABC-2 type transporter / ABC-2 type transporter / ABC transporter-like, conserved site / ABC transporters family signature. / ABC transporter / ABC transporter-like, ATP-binding domain / ATP-binding cassette, ABC transporter-type domain profile. / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Pleiotropic ABC efflux transporter of multiple drugs CDR1
Similarity search - Component
Biological speciesCandida albicans SC5314 (yeast)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.08 Å
AuthorsPeng Y / Sun H / Yan ZF
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2024
Title: Cryo-EM structures of Candida albicans Cdr1 reveal azole-substrate recognition and inhibitor blocking mechanisms.
Authors: Ying Peng / Yan Lu / Hui Sun / Jinying Ma / Xiaomei Li / Xiaodan Han / Zhixiong Fang / Junming Tan / Yingchen Qiu / Tingting Qu / Meng Yin / Zhaofeng Yan /
Abstract: In Candida albicans, Cdr1 pumps azole drugs out of the cells to reduce intracellular accumulation at detrimental concentrations, leading to azole-drug resistance. Milbemycin oxime, a veterinary anti- ...In Candida albicans, Cdr1 pumps azole drugs out of the cells to reduce intracellular accumulation at detrimental concentrations, leading to azole-drug resistance. Milbemycin oxime, a veterinary anti-parasitic drug, strongly and specifically inhibits Cdr1. However, how Cdr1 recognizes and exports azole drugs, and how milbemycin oxime inhibits Cdr1 remain unclear. Here, we report three cryo-EM structures of Cdr1 in distinct states: the apo state (Cdr1), fluconazole-bound state (Cdr1), and milbemycin oxime-inhibited state (Cdr1). Both the fluconazole substrate and the milbemycin oxime inhibitor are primarily recognized within the central cavity of Cdr1 through hydrophobic interactions. The fluconazole is suggested to be exported from the binding site into the environment through a lateral pathway driven by TM2, TM5, TM8 and TM11. Our findings uncover the inhibitory mechanism of milbemycin oxime, which inhibits Cdr1 through competition, hindering export, and obstructing substrate entry. These discoveries advance our understanding of Cdr1-mediated azole resistance in C. albicans and provide the foundation for the development of innovative antifungal drugs targeting Cdr1 to combat azole-drug resistance.
History
DepositionJul 22, 2024-
Header (metadata) releaseSep 18, 2024-
Map releaseSep 18, 2024-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_60910.png

Downloads & links

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Map

FileDownload / File: emd_60910.map.gz / Format: CCP4 / Size: 40.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.09 Å/pix.
x 220 pix.
= 239.36 Å		1.09 Å/pix.
x 220 pix.
= 239.36 Å		1.09 Å/pix.
x 220 pix.
= 239.36 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.088 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.79
Minimum - Maximum-3.0852535 - 5.1175947
Average (Standard dev.)0.010151004 (±0.14034672)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions220220220
Spacing220220220
CellA=B=C: 239.36002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_60910_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_60910_half_map_2.map
Projections & Slices
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Sample components

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Entire : The Cryo-EM structure of Candida albicans Cdr1 in milbemycin oxim...

EntireName: The Cryo-EM structure of Candida albicans Cdr1 in milbemycin oxime-inhibited state
Components
  • Complex: The Cryo-EM structure of Candida albicans Cdr1 in milbemycin oxime-inhibited state
    • Protein or peptide: Pleiotropic ABC efflux transporter of multiple drugs CDR1
  • Ligand: Pip2(20:4/18:0)
  • Ligand: milbemycin oxime

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Supramolecule #1: The Cryo-EM structure of Candida albicans Cdr1 in milbemycin oxim...

SupramoleculeName: The Cryo-EM structure of Candida albicans Cdr1 in milbemycin oxime-inhibited state
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Candida albicans SC5314 (yeast)

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Macromolecule #1: Pleiotropic ABC efflux transporter of multiple drugs CDR1

MacromoleculeName: Pleiotropic ABC efflux transporter of multiple drugs CDR1
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Candida albicans SC5314 (yeast)
Molecular weightTheoretical: 170.159656 KDa
Recombinant expressionOrganism: Saccharomyces cerevisiae (brewer's yeast)
SequenceString: MSDSKMSSQD ESKLEKAISQ DSSSENHSIN EYHGFDAHTS ENIQNLARTF THDSFKDDSS AGLLKYLTHM SEVPGVNPYE HEEINNDQL NPDSENFNAK FWVKNLRKLF ESDPEYYKPS KLGIGYRNLR AYGVANDSDY QPTVTNALWK LATEGFRHFQ K DDDSRYFD ...String:
MSDSKMSSQD ESKLEKAISQ DSSSENHSIN EYHGFDAHTS ENIQNLARTF THDSFKDDSS AGLLKYLTHM SEVPGVNPYE HEEINNDQL NPDSENFNAK FWVKNLRKLF ESDPEYYKPS KLGIGYRNLR AYGVANDSDY QPTVTNALWK LATEGFRHFQ K DDDSRYFD ILKSMDAIMR PGELTVVLGR PGAGCSTLLK TIAVNTYGFH IGKESQITYD GLSPHDIERH YRGDVIYSAE TD VHFPHLS VGDTLEFAAR LRTPQNRGEG IDRETYAKHM ASVYMATYGL SHTRNTNVGN DFVRGVSGGE RKRVSIAEAS LSG ANIQCW DNATRGLDSA TALEFIRALK TSAVILDTTP LIAIYQCSQD AYDLFDKVVV LYEGYQIFFG KATKAKEYFE KMGW KCPQR QTTADFLTSL TNPAEREPLP GYEDKVPRTA QEFETYWKNS PEYAELTKEI DEYFVECERS NTRETYRESH VAKQS NNTR PASPYTVSFF MQVRYGVARN FLRMKGDPSI PIFSVFGQLV MGLILSSVFY NLSQTTGSFY YRGAAMFFAV LFNAFS SLL EIMSLFEARP IVEKHKKYAL YRPSADALAS IISELPVKLA MSMSFNFVFY FMVNFRRNPG RFFFYWLMCI WCTFVMS HL FRSIGAVSTS ISGAMTPATV LLLAMVIYTG FVIPTPSMLG WSRWINYINP VGYVFESLMV NEFHGREFQC AQYVPSGP G YENISRSNQV CTAVGSVPGN EMVSGTNYLA GAYQYYNSHK WRNLGITIGF AVFFLAIYIA LTEFNKGAMQ KGEIVLFLK GSLKKHKRKT AASNKGDIEA GPVAGKLDYQ DEAEAVNNEK FTEKGSTGSV DFPENREIFF WRDLTYQVKI KKEDRVILDH VDGWVKPGQ ITALMGASGA GKTTLLNCLS ERVTTGIITD GERLVNGHAL DSSFQRSIGY VQQQDVHLET TTVREALQFS A YLRQSNKI SKKEKDDYVD YVIDLLEMTD YADALVGVAG EGLNVEQRKR LTIGVELVAK PKLLLFLDEP TSGLDSQTAW SI CKLMRKL ADHGQAILCT IHQPSALIMA EFDRLLFLQK GGRTAYFGEL GENCQTMINY FEKYGADPCP KEANPAEWML QVV GAAPGS HAKQDYFEVW RNSSEYQAVR EEINRMEAEL SKLPRDNDPE ALLKYAAPLW KQYLLVSWRT IVQDWRSPGY IYSK IFLVV SAALFNGFSF FKAKNNMQGL QNQMFSVFMF FIPFNTLVQQ MLPYFVKQRD VYEVREAPSR TFSWFAFIAG QITSE IPYQ VAVGTIAFFC WYYPLGLYNN ATPTDSVNPR GVLMWMLVTA FYVYTATMGQ LCMSFSELAD NAANLATLLF TMCLNF CGV LAGPDVLPGF WIFMYRCNPF TYLVQAMLST GLANTFVKCA EREYVSVKPP NGESCSTYLD PYIKFAGGYF ETRNDGS CA FCQMSSTNTF LKSVNSLYSE RWRNFGIFIA FIAINIILTV IFYWLARVPK GNREKKNKK

UniProtKB: Pleiotropic ABC efflux transporter of multiple drugs CDR1

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Macromolecule #2: Pip2(20:4/18:0)

MacromoleculeName: Pip2(20:4/18:0) / type: ligand / ID: 2 / Number of copies: 1 / Formula: A1L26
Molecular weightTheoretical: 1.047088 KDa

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Macromolecule #3: milbemycin oxime

MacromoleculeName: milbemycin oxime / type: ligand / ID: 3 / Number of copies: 1 / Formula: A1L27
Molecular weightTheoretical: 555.702 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 55.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.1 µm / Nominal defocus min: 1.5 µm

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.08 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 427519
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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