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- PDB-8ynz: The structure of EfpA_BRD-8000.3 complex -

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Basic information

Entry
Database: PDB / ID: 8ynz
TitleThe structure of EfpA_BRD-8000.3 complex
ComponentsUncharacterized MFS-type transporter EfpA
KeywordsPROTEIN BINDING
Function / homology
Function and homology information


transmembrane transporter activity / membrane / plasma membrane
Similarity search - Function
Major facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
: / Uncharacterized MFS-type transporter EfpA
Similarity search - Component
Biological speciesMycobacterium tuberculosis H37Rv (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.41 Å
AuthorsLi, D.L. / Sun, J.Q.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82272379 China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2024
Title: Structure and function of EfpA as a lipid transporter and its inhibition by BRD-8000.3.
Authors: Delin Li / Xiaokang Zhang / Yuanhang Yao / Xue Sun / Junqing Sun / Xiaomin Ma / Kai Yuan / Guijie Bai / Xuefei Pang / Rongmao Hua / Tianling Guo / Yuqian Mi / Lingzhi Wu / Jie Zhang / Yan Wu ...Authors: Delin Li / Xiaokang Zhang / Yuanhang Yao / Xue Sun / Junqing Sun / Xiaomin Ma / Kai Yuan / Guijie Bai / Xuefei Pang / Rongmao Hua / Tianling Guo / Yuqian Mi / Lingzhi Wu / Jie Zhang / Yan Wu / Yingxia Liu / Peiyi Wang / Catherine C L Wong / Xiao-Wei Chen / Haixia Xiao / George Fu Gao / Feng Gao /
Abstract: EfpA, the first major facilitator superfamily (MFS) protein identified in (Mtb), is an essential efflux pump implicated in resistance to multiple drugs. EfpA-inhibitors have been developed to kill ...EfpA, the first major facilitator superfamily (MFS) protein identified in (Mtb), is an essential efflux pump implicated in resistance to multiple drugs. EfpA-inhibitors have been developed to kill drug-tolerant Mtb. However, the biological function of EfpA has not yet been elucidated. Here, we present the cryo-EM structures of EfpA complexed with lipids or the inhibitor BRD-8000.3 at resolutions of 2.9 Å and 3.4 Å, respectively. Unexpectedly, EfpA forms an antiparallel dimer. Functional studies reveal that EfpA is a lipid transporter and BRD-8000.3 inhibits its lipid transport activity. Intriguingly, the mutation V319F, known to confer resistance to BRD-8000.3, alters the expression level and oligomeric state of EfpA. Based on our results and the observation of other antiparallel dimers in the MFS family, we propose an antiparallel-function model of EfpA. Collectively, our work provides structural and functional insights into EfpA's role in lipid transport and drug resistance, which would accelerate the development of antibiotics against this promising drug target.
History
DepositionMar 12, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Dec 4, 2024Provider: repository / Type: Initial release
Revision 1.0Dec 4, 2024Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Dec 4, 2024Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Dec 4, 2024Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Dec 4, 2024Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jul 16, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jul 16, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Uncharacterized MFS-type transporter EfpA
B: Uncharacterized MFS-type transporter EfpA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)120,1454
Polymers119,3432
Non-polymers8032
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Uncharacterized MFS-type transporter EfpA / Efflux protein A


Mass: 59671.445 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis H37Rv (bacteria)
Gene: efpA, Rv2846c / Production host: Schizosaccharomyces pombe (fission yeast) / References: UniProt: P9WJY5
#2: Chemical ChemComp-A1AQR / (1S,3S)-N-[6-bromo-5-(pyrimidin-2-yl)pyridin-2-yl]-2,2-dimethyl-3-(2-methylprop-1-en-1-yl)cyclopropane-1-carboxamide


Mass: 401.300 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H21BrN4O / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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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: EfpA / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) (bacteria)
Source (recombinant)Organism: Schizosaccharomyces pombe (fission 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

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm / Cs: 0.001 mm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.41 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 180121 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0037076
ELECTRON MICROSCOPYf_angle_d0.5479650
ELECTRON MICROSCOPYf_dihedral_angle_d5.341020
ELECTRON MICROSCOPYf_chiral_restr0.0371188
ELECTRON MICROSCOPYf_plane_restr0.0051192

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