Pathway and mechanism of drug binding to G-protein-coupled receptors

被引:573
作者
Dror, Ron O. [1 ]
Pan, Albert C. [1 ]
Arlow, Daniel H. [1 ]
Borhani, David W. [1 ]
Maragakis, Paul [1 ]
Shan, Yibing [1 ]
Xu, Huafeng [1 ]
Shaw, David E. [1 ,2 ]
机构
[1] DE Shaw Res, New York, NY 10036 USA
[2] Columbia Univ, Ctr Computat Biol & Bioinformat, New York, NY 10032 USA
关键词
dewetting; kinetics; ligands; drug target; alprenolol; BETA-ADRENERGIC-RECEPTORS; BETA(2)-ADRENERGIC RECEPTOR; LIGAND-BINDING; SITE; DISCOVERY; SUBSTRATE; MEMBRANES; DYNAMICS; AGONISTS;
D O I
10.1073/pnas.1104614108
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
How drugs bind to their receptors-from initial association, through drug entry into the binding pocket, to adoption of the final bound conformation, or "pose"-has remained unknown, even for G-protein-coupled receptor modulators, which constitute one-third of all marketed drugs. We captured this pharmaceutically critical process in atomic detail using the first unbiased molecular dynamics simulations in which drug molecules spontaneously associate with G-protein-coupled receptors to achieve final poses matching those determined crystallographically. We found that several beta blockers and a beta agonist all traverse the same well-defined, dominant pathway as they bind to the beta(1)- and beta(2)-adrenergic receptors, initially making contact with a vestibule on each receptor's extracellular surface. Surprisingly, association with this vestibule, at a distance of 15 angstrom from the binding pocket, often presents the largest energetic barrier to binding, despite the fact that subsequent entry into the binding pocket requires the receptor to deform and the drug to squeeze through a narrow passage. The early barrier appears to reflect the substantial dehydration that takes place as the drug associates with the vestibule. Our atomic-level description of the binding process suggests opportunities for allosteric modulation and provides a structural foundation for future optimization of drug-receptor binding and unbinding rates.
引用
收藏
页码:13118 / 13123
页数:6
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