A Structural Insight into the Reorientation of Transmembrane Domains 3 and 5 during Family A G Protein-Coupled Receptor Activation

被引：54

作者：

Sansuk, Kamonchanok ^{[1
]}

Deupi, Xavier ^{[2
]}

Torrecillas, Ivan R. ^{[2
]}

Jongejan, Aldo ^{[1
]}

Nijmeijer, Saskia ^{[1
]}

Bakker, Remko A. ^{[1
]}

Pardo, Leonardo ^{[2
]}

Leurs, Rob ^{[1
]}

机构：

[1] Vrije Univ Amsterdam, Dept Med Chem, Leiden Amsterdam Ctr Drug Res, NL-1081 HV Amsterdam, Netherlands

[2] Univ Autonoma Barcelona, Fac Med, Lab Med Comptac, Unitat Bioestadist, Bellaterra, Spain

来源：

MOLECULAR PHARMACOLOGY | 2011年 / 79卷 / 02期

关键词：

CONSTITUTIVELY ACTIVE MUTANTS; CRYSTAL-STRUCTURE; BETA(2)-ADRENERGIC RECEPTOR; RHODOPSIN FAMILY; AGONIST BINDING; REVEALS; CONFORMATION; MUTAGENESIS; RESIDUES; HELICES;

D O I：

10.1124/mol.110.066068

中图分类号：

R9 [药学];

学科分类号：

100702 [药剂学];

摘要：

Rearrangement of transmembrane domains (TMs) 3 and 5 after agonist binding is necessary for stabilization of the active state of class A G protein-coupled receptors (GPCRs). Using site-directed mutagenesis and functional assays, we provide the first evidence that the TAS(I/V) sequence motif at positions 3.37 to 3.40, highly conserved in aminergic receptors, plays a key role in the activation of the histamine H 1 receptor. By combining these data with structural information from X-ray crystallography and computational modeling, we suggest that Thr(3.37) interacts with TM5, stabilizing the inactive state of the receptor, whereas the hydrophobic side chain at position 3.40, highly conserved in the whole class A GPCR family, facilitates the reorientation of TM5. We propose that the structural change of TM5 during the process of GPCR activation involves a local Pro(5.50)-induced unwinding of the helix, acting as a hinge, and the highly conserved hydrophobic Ile(3.40) side chain, acting as a pivot.

引用

页码：262 / 269

页数：8

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