Allosteric modulation in monomers and oligomers of a G protein-coupled receptor

被引：19

作者：

Shivnaraine, Rabindra V. ^{[1
,6
]}

Kelly, Brendan ^{[1
,7
]}

Sankar, Krishana S. ^{[2
]}

Redka, Dar'ya S. ^{[1
]}

Han, Yi Rang ^{[1
]}

Huang, Fei ^{[1
]}

Elmslie, Gwendolynne ^{[3
,4
]}

Pinto, Daniel ^{[1
]}

Li, Yuchong ^{[5
]}

Rocheleau, Jonathan V. ^{[2
]}

Gradinaru, Claudiu C. ^{[5
]}

Ellis, John ^{[3
,4
]}

Wells, James W. ^{[1
]}

机构：

[1] Univ Toronto, Leslie Dan Fac Pharm, Dept Pharmaceut Sci, Toronto, ON, Canada

[2] Univ Toronto, Dept Physiol, Toronto, ON, Canada

[3] Hershey Med Ctr, Dept Psychiat, Hershey, PA 17033 USA

[4] Hershey Med Ctr, Dept Pharmacol, Hershey, PA 17033 USA

[5] Univ Toronto, Dept Phys, Toronto, ON, Canada

[6] Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA

[7] Stanford Univ, Dept Comp Sci, Stanford, CA 94305 USA

来源：

ELIFE | 2016年 / 5卷

基金：

加拿大健康研究院; 加拿大自然科学与工程研究理事会; 美国国家卫生研究院;

关键词：

MUSCARINIC ACETYLCHOLINE-RECEPTOR; CHOLINERGIC-RECEPTOR; BINDING-PROPERTIES; COOPERATIVITY; GALLAMINE; FLUORESCENCE; ANTAGONIST; COMPLEXES; CELLS;

D O I：

10.7554/eLife.11685

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The M-2 muscarinic receptor is the prototypic model of allostery in GPCRs, yet the molecular and the supramolecular determinants of such effects are unknown. Monomers and oligomers of the M-2 muscarinic receptor therefore have been compared to identify those allosteric properties that are gained in oligomers. Allosteric interactions were monitored by means of a FRET-based sensor of conformation at the allosteric site and in pharmacological assays involving mutants engineered to preclude intramolecular effects. Electrostatic, steric, and conformational determinants of allostery at the atomic level were examined in molecular dynamics simulations. Allosteric effects in monomers were exclusively negative and derived primarily from intramolecular electrostatic repulsion between the allosteric and orthosteric ligands. Allosteric effects in oligomers could be positive or negative, depending upon the allosteric-orthosteric pair, and they arose from interactions within and between the constituent protomers. The complex behavior of oligomers is characteristic of muscarinic receptors in myocardial preparations.

引用

页数：26

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