Evidence map›Paper›PMID 40169593›Full record

ArticleNature communications2025

Structure and inhibition mechanisms of Mycobacterium tuberculosis essential transporter efflux protein A.

Nitesh Kumar Khandelwal, Meghna Gupta, James E Gomez, Sulyman Barkho, Ziqiang Guan, Ashley Y Eng, Tomohiko Kawate, Sree Ganesh Balasubramani, Andrej Sali, Deborah T Hung and 1 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Structural basis of disease mutation and substrate recognition by the human SLC2A9 transporter.Proceedings of the National Academy of Sciences of the United States of America · 2025
    Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

11 authors.

Nitesh Kumar Khandelwal *Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA.ORCID http://orcid.org/0000-0002-6319-8048
Meghna Gupta *Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA.ORCID http://orcid.org/0000-0002-7432-3211
James E GomezBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Sulyman BarkhoBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Ziqiang GuanDepartment of Biochemistry, Duke University Medical Center, Durham, NC, USA.ORCID http://orcid.org/0000-0002-8082-3423
Ashley Y EngBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Tomohiko KawateBroad Institute of MIT and Harvard, Cambridge, MA, USA.
Sree Ganesh BalasubramaniDepartment of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
Andrej SaliDepartment of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.ORCID http://orcid.org/0000-0003-0435-6197
Deborah T HungBroad Institute of MIT and Harvard, Cambridge, MA, USA. hung@molbio.mgh.harvard.edu.ORCID http://orcid.org/0000-0003-4262-0673
Robert M StroudDepartment of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA. stroud@msg.ucsf.edu.ORCID http://orcid.org/0000-0003-2083-5665

Funding

STRUCTURE/FUNCTION OF PROTEINS AT MOLECULAR LEVELR01GM024485 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI STROUD, ROBERT M · 1985 to 2024
$7.5M
Molecular Basis for Transmembrane Conduction & SignalingR37GM024485 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI STROUD, ROBERT M · 2007 to 2016
$4.7M
Roles of novel cationic lipids in bacterial pathogenesisR01AI178692 · NIAID · UNIVERSITY OF TEXAS DALLAS · PI Kelly S Doran, Ziqiang Guan · 2023 to 2026
$2.6M
Adaptive alterations of lipids in mitis group streptococciR01AI148366 · NIAID · UNIVERSITY OF TEXAS DALLAS · PI GUAN, ZIQIANG, PALMER, KELLI LEA · 2020 to 2024
$2.5M
Acquisition of an electron microscope for high-resolution single particle cryo-EMS10OD021741 · OD · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CHENG, YIFAN · 2016 to 2016
$2.0M
Glacios™ Cryo Transmission Electron Microscope with 200 kV XFEG opticsS10OD026881 · OD · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CHENG, YIFAN · 2019 to 2019
$1.8M
Linux cluster for near atomic resolution single particle cryo-EMS10OD020054 · OD · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CHENG, YIFAN · 2015 to 2015
$456k
NIAID NIH HHS R01 AI148366NIAID NIH HHS R01 AI178692NIGMS NIH HHS R01 GM024485NIGMS NIH HHS R37 GM024485NIH HHS S10 OD020054NIH HHS S10 OD021741NIH HHS S10 OD026881
6 · The paper itself

Abstract

A broad chemical genetic screen in Mycobacterium tuberculosis (Mtb) identified compounds (BRD-8000.3 and BRD-9327) that inhibit the essential efflux pump EfpA. To understand the mechanisms of inhibition, we determined the structures of EfpA with these inhibitors bound at 2.7-3.4 Å resolution. Our structures reveal different mechanisms of inhibition by the two inhibitors. BRD-8000.3 binds in a tunnel contacting the lipid bilayer and extending toward the central cavity to displace the fatty acid chain of a lipid molecule bound in the apo structure, suggesting its blocking of an access route for a natural lipidic substrate. Meanwhile, BRD-9327 binds in the outer vestibule without complete blockade of the substrate path to the outside, suggesting its possible inhibition of the movement necessary for alternate access of the transporter. Our results show EfpA as a potential lipid transporter, explain the basis of the synergy of these inhibitors and their potential for combination anti-tuberculosis therapy.

Indexed as

Antitubercular AgentsBacterial ProteinsMembrane Transport ProteinsMycobacterium tuberculosisCrystallography, X-RayModels, MolecularAntitubercular AgentsBacterial ProteinsMembrane Transport Proteins

Identifiers

PMID40169593
PMCPMC11961569

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.