9CTF

SapNP Reconstituted Human ABCB1 bound to Taxol in presence of ATP

Summary for 9CTF

• Entry DOI: 10.2210/pdb9ctf/pdb
• Related: 9CR8 9CTC
• EMDB information: 45854 45903 45904
• Descriptor: ATP-dependent translocase ABCB1, UNKNOWN BRANCHED FRAGMENT OF PHOSPHOLIPID, ADENOSINE-5'-TRIPHOSPHATE, ... (4 entities in total)
• Functional Keywords: abcb1, p-gp, substrate bound, nanoparticle, saposin a, taxol bound, membrane protein, php, mdr1, translocase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 153542.11

Authors

Kurre, D.,Alam, A. (deposition date: 2024-07-25, release date: 2025-01-22, Last modification date: 2025-05-21)

Primary citation

Kurre, D.,Dang, P.X.,Le, L.T.M.,Gadkari, V.V.,Alam, A.
Structural insights into binding-site access and ligand recognition by human ABCB1.
Embo J., 44:991-1006, 2025

PubMed 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.

PubMed: 39806099
DOI: 10.1038/s44318-025-00361-z

Experimental method

ELECTRON MICROSCOPY (3.9 Å)