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- PDB-9ium: The structure of Candida albicans Cdr1 in milbemycin oxime-inhibi... -

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Entry
Database: PDB / ID: 9ium
TitleThe structure of Candida albicans Cdr1 in milbemycin oxime-inhibited state
ComponentsPleiotropic ABC efflux transporter of multiple drugs CDR1
KeywordsTRANSPORT PROTEIN / ABC transporters / Pleiotropic drug resistance / Membrane 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.08 Å
AuthorsPeng, Y. / Sun, H. / Yan, Z.F.
Funding support1items
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, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 18, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Pleiotropic ABC efflux transporter of multiple drugs CDR1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)171,7623
Polymers170,1601
Non-polymers1,6032
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Pleiotropic ABC efflux transporter of multiple drugs CDR1 / Pleiotropic drug resistance protein CDR1


Mass: 170159.656 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Candida albicans SC5314 (yeast) / Gene: CDR1, CAALFM_C305220WA, CaO19.13421, CaO19.6000 / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: Q5ANA3
#2: Chemical ChemComp-A1L26 / Pip2(20:4/18:0) / [(2R)-3-[hydroxy-[(1S,5S)-2,3,6-trihydroxy-4,5-diphosphonooxycyclohexyl]oxyphosphoryl]oxy-2-octadecanoyloxypropyl] (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate / Phosphatidylinositol Diphosphate(20:4n6/18:0)


Mass: 1047.088 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C47H85O19P3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-A1L27 / milbemycin oxime / (1~{R},4~{S},5'~{S},6~{R},6'~{R},8~{R},10~{E},10~{R},13~{R},14~{E},16~{E},21~{Z},24~{S})-6'-ethyl-21-hydroxyimino-5',11,13,22-tetramethyl-24-oxidanyl-spiro[3,7,19-trioxatetracyclo[15.6.1.1^{4,8}.1^{20,24}]pentacosa-10,14,16,22-tetraene-6,2'-oxane]-2-one / Milbemycin A4 oxime


Mass: 555.702 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H45NO7 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: The Cryo-EM structure of Candida albicans Cdr1 in milbemycin oxime-inhibited state
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Candida albicans SC5314 (yeast)
Source (recombinant)Organism: Saccharomyces cerevisiae (brewer's yeast)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

MicroscopyModel: FEI TITAN
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2100 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 55 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.08 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 427519 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 74.92 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.002511083
ELECTRON MICROSCOPYf_angle_d0.4615032
ELECTRON MICROSCOPYf_chiral_restr0.03741619
ELECTRON MICROSCOPYf_plane_restr0.00311912
ELECTRON MICROSCOPYf_dihedral_angle_d9.6271564

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