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Structural insight into binding site access and ligand recognition by human ABCB1
Open accessPreprint — published as 10.1038/s44318-025-00361-z · Paper page
Abstract
ABCB1 is a broad-spectrum efflux pump central to cellular drug handling and multidrug resistance in humans. However, its mechanisms of poly-specific substrate recognition and transport remain poorly resolved. Here we present cryo-EM structures of lipid embedded human ABCB1 in its apo, substrate-bound, inhibitor-bound, and nucleotide-trapped states at 3.4-3.9 Å resolution without using stabilizing antibodies or mutations and each revealing a distinct conformation. The substrate binding site is located within one half of the molecule and, in the apo state, is obstructed by transmembrane helix (TM) 4. Substrate and inhibitor binding are distinguished by major differences in TM arrangement and ligand binding chemistry, with TM4 playing a central role in all conformational transitions. Our data offer fundamental new insights into the role structural asymmetry, secondary structure breaks, and lipid interactions play in ABCB1 function and have far-reaching implications for ABCB1 inhibitor design and predicting its substrate binding profiles.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
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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
- Venue
- The EMBO Journal
- Publisher
- openRxiv
- Published
- 2024-08-12
- Volume
- 44
- Issue
- 4
- Pages
- 991-1006
- ISSN
- 0261-4189 (ISSN-L)
- PMC
- PMC11833089
- OpenAlex
- W4406302997
- Cited by
- 25
- References
- 1
- Citations by year
- 2026: 15 · 2025: 10
- FWCI
- 10.29
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- 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
- Hormel Foundation
- University of Minnesota
- National Institutes of Health
- National Institute of General Medical Sciences (R01GM146906)
- 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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