Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor

被引:388
作者
Bokoch, Michael P. [1 ]
Zou, Yaozhong [1 ]
Rasmussen, Soren G. F. [1 ]
Liu, Corey W. [2 ]
Nygaard, Rie [1 ]
Rosenbaum, Daniel M. [1 ]
Fung, Juan Jose [1 ]
Choi, Hee-Jung [1 ,3 ]
Thian, Foon Sun [1 ]
Kobilka, Tong Sun [1 ]
Puglisi, Joseph D. [2 ,3 ]
Weis, William I. [1 ,3 ]
Pardo, Leonardo [4 ]
Prosser, R. Scott [5 ]
Mueller, Luciano [6 ]
Kobilka, Brian K. [1 ]
机构
[1] Stanford Univ, Dept Mol & Cellular Physiol, Sch Med, Stanford, CA 94305 USA
[2] Stanford Univ, Stanford Magnet Resonance Lab, Sch Med, Stanford, CA 94305 USA
[3] Stanford Univ, Dept Biol Struct, Sch Med, Stanford, CA 94305 USA
[4] Univ Autonoma Barcelona, Lab Med Computac, Unitat Bioestadist, E-08193 Barcelona, Spain
[5] Univ Toronto, UTM, Dept Chem, Mississauga, ON L5L 1C6, Canada
[6] Bristol Myers Squibb Co, Pharmaceut Res Inst, Princeton, NJ 08543 USA
基金
美国国家卫生研究院;
关键词
TOGGLE SWITCH MODEL; CRYSTAL-STRUCTURE; BINDING-SITE; BETA(2)-ADRENERGIC RECEPTOR; ADRENERGIC-RECEPTOR; LYSINE RESIDUES; HELIX MOVEMENT; ACTIVATION; RHODOPSIN; RECOGNITION;
D O I
10.1038/nature08650
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
G-protein-coupled receptors (GPCRs) are seven-transmembrane proteins that mediate most cellular responses to hormones and neurotransmitters. They are the largest group of therapeutic targets for a broad spectrum of diseases. Recent crystal structures of GPCRs(1-5) have revealed structural conservation extending from the orthosteric ligand-binding site in the transmembrane core to the cytoplasmic G-protein-coupling domains. In contrast, the extracellular surface (ECS) of GPCRs is remarkably diverse and is therefore an ideal target for the discovery of subtype-selective drugs. However, little is known about the functional role of the ECS in receptor activation, or about conformational coupling of this surface to the native ligand-binding pocket. Here we use NMR spectroscopy to investigate ligand-specific conformational changes around a central structural feature in the ECS of the beta(2) adrenergic receptor: a salt bridge linking extracellular loops 2 and 3. Small-molecule drugs that bind within the transmembrane core and exhibit different efficacies towards G-protein activation (agonist, neutral antagonist and inverse agonist) also stabilize distinct conformations of the ECS. We thereby demonstrate conformational coupling between the ECS and the orthosteric binding site, showing that drugs targeting this diverse surface could function as allosteric modulators with high subtype selectivity. Moreover, these studies provide a new insight into the dynamic behaviour of GPCRs not addressable by static, inactive-state crystal structures.
引用
收藏
页码:108 / U121
页数:7
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