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Cited by 25Drug Transport and Resistance MechanismsAntibiotic Resistance in BacteriaProtein Structure and Dynamics

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Structural insights into binding-site access and ligand recognition by human ABCB1

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Kurre, Devanshu, Dang, Phuoc X, Le, Le T M, Gadkari, Varun V, Alam, Amer·2025·The EMBO Journal
DOI 10.1038/s44318-025-00361-zPMC PMC11833089

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Abstract

ABCB1 is a broad-spectrum efflux pump central to cellular drug handling and multidrug resistance in humans. However, how it is able to recognize and transport a wide range of diverse substrates remains poorly understood. Here we present cryo-EM structures of lipid-embedded human ABCB1 in conformationally distinct apo-, substrate-bound, inhibitor-bound, and nucleotide-trapped states at 3.4–3.9 Å resolution, in the absence of stabilizing antibodies or mutations. The substrate-binding site is located within one half of the molecule and, in the apo state, is obstructed by the transmembrane helix (TM) 4. Substrate and inhibitor binding are distinguished by major TM rearrangements and their ligand binding chemistry, with TM4 playing a central role in all conformational transitions. Furthermore, our data identify secondary structure-breaking residues that impart localized TM flexibility and asymmetry between the two transmembrane domains. The resulting structural changes and lipid interactions that are induced by substrate and inhibitor binding can predict substrate-binding profiles and may direct ABCB1 inhibitor design.

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Metadata

Authors
Kurre, D., Dang, P. X., Le, L. T. M., Gadkari, V. V., & Alam, A.
Affiliations
University of Minnesota (US)
Corresponding author
Alam, Amer
ORCID
Venue
The EMBO Journal
Publisher
Springer Science and Business Media LLC
Published
2025-01-13
Volume
44
Issue
4
Pages
991-1006
ISSN
  • 0261-4189 (ISSN-L)
  • 1460-2075
DOI
10.1038/s44318-025-00361-z
PMC
PMC11833089
OpenAlex
W4406302997
Cited by
25
References
6
Citations by year
2026: 15 · 2025: 10
FWCI
10.35
Type
journal article
Language
en
Open access
Licence
Locations
  • The EMBO Journal (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • HHS | NIH | National Institute of General Medical Sciences (1R01GM146906)
  • Hormel Foundation
  • University of Minnesota Startup Funds
  • Eagles Telethon Postdoctoral Fellowship
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Health Sciences › Medicine › Microbiology (medical) › Antibiotic Resistance in Bacteria
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
P-glycoprotein, multidrug resistance, drug efflux pumps, substrate binding site, ligand recognition, conformational change, P-glycoprotein inhibitors, lipid interactions, cryo-EM structure

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