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Updated: Jun 2, 2025
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Real Time Measurements of Membrane Protein:Receptor Interactions Using Surface Plasmon Resonance SPR
Published on: November 29, 2014
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Structural insights into binding-site access and ligand recognition by human ABCB1.
Devanshu Kurre1, Phuoc X Dang1,2, Le T M Le1,3
1The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA.
The EMBO Journal
|January 13, 2025
Summary
Human ABCB1 efflux pump structures reveal how it transports diverse drugs. Understanding these mechanisms, particularly TM4 rearrangements, can guide the development of new multidrug resistance inhibitors.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Pharmacology
Background:
- The ATP-binding cassette subfamily B member 1 (ABCB1) protein is crucial for drug transport and multidrug resistance.
- The precise mechanisms by which ABCB1 recognizes and transports a wide array of substrates are not fully understood.
Purpose of the Study:
- To elucidate the structural basis of ABCB1 substrate recognition and transport.
- To investigate the conformational dynamics of ABCB1 in various functional states.
Main Methods:
- Cryo-electron microscopy (cryo-EM) was used to determine high-resolution structures of lipid-embedded human ABCB1.
- Structures were obtained in apo, substrate-bound, inhibitor-bound, and nucleotide-trapped states.
Main Results:
- The substrate-binding site is located in one half of ABCB1 and is initially obstructed by transmembrane helix 4 (TM4).
- Major transmembrane rearrangements, involving TM4, distinguish substrate and inhibitor binding.
- Specific residues create localized flexibility and asymmetry within the transmembrane domains, influencing substrate binding.
Conclusions:
- Structural insights into ABCB1 conformational changes and lipid interactions can predict substrate-binding profiles.
- These findings provide a foundation for designing novel ABCB1 inhibitors to combat multidrug resistance.
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