Structure of a Class C GPCR Metabotropic Glutamate Receptor 1 Bound to an Allosteric Modulator

被引：417

作者：

Wu, Huixian ^{[1
]}

Wang, Chong ^{[1
]}

Gregory, Karen J. ^{[2
,3
,4
]}

Han, Gye Won ^{[1
]}

Cho, Hyekyung P. ^{[2
,3
]}

Xia, Yan ^{[5
,6
,7
]}

Niswender, Colleen M. ^{[2
,3
]}

Katritch, Vsevolod ^{[1
]}

Meiler, Jens ^{[5
,6
,7
]}

Cherezov, Vadim ^{[1
]}

Conn, P. Jeffrey ^{[2
,3
]}

Stevens, Raymond C. ^{[1
]}

机构：

[1] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA

[2] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Med Ctr, Vanderbilt Ctr Neurosci Drug Discovery, Nashville, TN 37232 USA

[4] Monash Univ, Monash Inst Pharmaceut Sci, Parkville, Vic, Australia

[5] Vanderbilt Univ, Med Ctr, Ctr Struct Biol, Nashville, TN 37232 USA

[6] Vanderbilt Univ, Med Ctr, Dept Chem, Nashville, TN 37232 USA

[7] Vanderbilt Univ, Med Ctr, Inst Chem Biol, Nashville, TN 37232 USA

来源：

SCIENCE | 2014年 / 344卷 / 6179期

基金：

澳大利亚国家健康与医学研究理事会; 美国国家科学基金会;

关键词：

PROTEIN-COUPLED RECEPTOR; PHARMACOLOGICAL CHARACTERIZATION; NONCOMPETITIVE ANTAGONISTS; BINDING POCKETS; SMALL-MOLECULE; DISCOVERY; ACTIVATION; EXPRESSION; DIVERSITY; AFFINITY;

D O I：

10.1126/science.1249489

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：

The excitatory neurotransmitter glutamate induces modulatory actions via the metabotropic glutamate receptors (mGlus), which are class C G protein-coupled receptors (GPCRs). We determined the structure of the human mGlu(1) receptor seven-transmembrane (7TM) domain bound to a negative allosteric modulator, FITM, at a resolution of 2.8 angstroms. The modulator binding site partially overlaps with the orthosteric binding sites of class A GPCRs but is more restricted than most other GPCRs. We observed a parallel 7TM dimer mediated by cholesterols, which suggests that signaling initiated by glutamate's interaction with the extracellular domain might be mediated via 7TM interactions within the full-length receptor dimer. A combination of crystallography, structure-activity relationships, mutagenesis, and full-length dimer modeling provides insights about the allosteric modulation and activation mechanism of class C GPCRs.

引用

页码：58 / 64

页数：7

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