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Structure of a zosuquidar and UIC2-bound human-mouse chimeric ABCB1
Amer Alam1, Raphael Küng2, Julia Kowal1
1Institute of Molecular Biology and Biophysics, ETH Zürich, 8093 Zürich, Switzerland.
Abstract:
The multidrug transporter ABCB1 (P-glycoprotein) is an ATP-binding cassette transporter that has a key role in protecting tissues from toxic insult and contributes to multidrug extrusion from cancer cells. Here, we report the near-atomic resolution cryo-EM structure of nucleotide-free ABCB1 trapped by an engineered disulfide cross-link between the nucleotide-binding domains (NBDs) and bound to the antigen-binding fragment of the human-specific inhibitory antibody UIC2 and to the third-generation ABCB1 inhibitor zosuquidar. Our structure reveals the transporter in an occluded conformation with a central, enclosed, inhibitor-binding pocket lined by residues from all transmembrane (TM) helices of ABCB1. The pocket spans almost the entire width of the lipid membrane and is occupied exclusively by two closely interacting zosuquidar molecules. The external, conformational epitope facilitating UIC2 binding is also visualized, providing a basis for its inhibition of substrate efflux. Additional cryo-EM structures suggest concerted movement of TM helices from both halves of the transporters associated with closing the NBD gap, as well as zosuquidar binding. Our results define distinct recognition interfaces of ABCB1 inhibitory agents, which may be exploited for therapeutic purposes.
Insights
The cryo-EM structure of the ABCB1 transporter reveals its occluded conformation and drug-binding pocket, offering insights into multidrug resistance mechanisms and inhibitor design.
Area of Science:
- Structural Biology
- Biochemistry
- Pharmacology
Background:
- ABCB1 (P-glycoprotein) is a crucial ATP-binding cassette transporter involved in multidrug resistance and tissue protection.
- Understanding ABCB1's structure is vital for developing strategies to overcome multidrug resistance in cancer therapy.
Purpose of the Study:
- To determine the near-atomic resolution cryo-EM structure of nucleotide-free ABCB1.
- To visualize the binding of the inhibitor zosuquidar and the antibody UIC2 to ABCB1.
- To elucidate the structural basis for ABCB1 inhibition and substrate efflux.
Main Methods:
- Cryo-electron microscopy (cryo-EM) at near-atomic resolution.
- Engineered disulfide cross-link to trap nucleotide-free ABCB1.
- Co-crystallization with UIC2 antibody fragment and zosuquidar inhibitor.
Main Results:
- The structure reveals an occluded ABCB1 conformation with a central, enclosed inhibitor-binding pocket.
- Two zosuquidar molecules were found within the pocket, spanning the lipid membrane.
- The binding site for the inhibitory antibody UIC2 was identified, explaining its mechanism.
Conclusions:
- The study defines the structural basis of ABCB1 inhibition by zosuquidar and UIC2.
- Distinct recognition interfaces for ABCB1 inhibitory agents were identified.
- These findings may guide the development of novel therapeutic strategies targeting ABCB1.
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