Structural Basis for Allosteric Regulation of GPCRs by Sodium Ions

被引:977
|
作者
Liu, Wei [1 ]
Chun, Eugene [1 ]
Thompson, Aaron A. [1 ]
Chubukov, Pavel [1 ]
Xu, Fei [1 ]
Katritch, Vsevolod [1 ]
Han, Gye Won [1 ]
Roth, Christopher B. [2 ]
Heitman, Laura H. [3 ]
IJzerman, Adriaan P. [3 ]
Cherezov, Vadim [1 ]
Stevens, Raymond C. [1 ]
机构
[1] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA
[2] Receptos, San Diego, CA 92121 USA
[3] Leiden Amsterdam Ctr Drug Res, Div Med Chem, NL-2300 RA Leiden, Netherlands
基金
荷兰研究理事会;
关键词
ADENOSINE A(2A) RECEPTOR; CRYSTAL-STRUCTURE; OPIOID RECEPTOR; MODULATION; RHODOPSIN; COMPLEX; AMILORIDE; RESIDUES; SITE;
D O I
10.1126/science.1219218
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
Pharmacological responses of G protein-coupled receptors (GPCRs) can be fine-tuned by allosteric modulators. Structural studies of such effects have been limited due to the medium resolution of GPCR structures. We reengineered the human A(2A) adenosine receptor by replacing its third intracellular loop with apocytochrome b(562)RIL and solved the structure at 1.8 angstrom resolution. The high-resolution structure allowed us to identify 57 ordered water molecules inside the receptor comprising three major clusters. The central cluster harbors a putative sodium ion bound to the highly conserved aspartate residue Asp(2.50). Additionally, two cholesterols stabilize the conformation of helix VI, and one of 23 ordered lipids intercalates inside the ligand-binding pocket. These high-resolution details shed light on the potential role of structured water molecules, sodium ions, and lipids/cholesterol in GPCR stabilization and function.
引用
收藏
页码:232 / 236
页数:6
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