Structures of Human A1 and A2A Adenosine Receptors with Xanthines Reveal Determinants of Selectivity

被引：166

作者：

Cheng, Robert K. Y. ^{[1
,2
]}

Segala, Elena ^{[1
]}

Robertson, Nathan ^{[1
]}

Deflorian, Francesca ^{[1
]}

Dore, Andrew S. ^{[1
]}

Errey, James C. ^{[1
]}

Fiez-Vandal, Cedric ^{[1
]}

Marshall, Fiona H. ^{[1
]}

Cooke, Robert M. ^{[1
]}

机构：

[1] Heptares Therapeut Ltd, Biopk,Broadwater Rd, Welwyn Garden City AL7 3AX, Herts, England

[2] LeadXpro AG, Pk InnovAARE, CH-5234 Villigen, Switzerland

来源：

STRUCTURE | 2017年 / 25卷 / 08期

关键词：

2ND EXTRACELLULAR LOOP; HIGH-AFFINITY ANTAGONIST; SPECIES-DIFFERENCES; CRYSTAL-STRUCTURE; AGONIST; BINDING; LIGANDS; A(1)-ADENOSINE; RADIOLIGAND; FEATURES;

D O I：

10.1016/j.str.2017.06.012

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The adenosine A(1) and A(2A) receptors belong to the purinergic family of G protein-coupled receptors, and regulate diverse functions of the cardiovascular, respiratory, renal, inflammation, and CNS. Xanthines such as caffeine and theophylline are weak, nonselective antagonists of adenosine receptors. Here we report the structure of a thermostabilized human A(1) receptor at 3.3 angstrom resolution with PSB36, an A(1)-selective xanthine-based antagonist. This is compared with structures of the A(2A) receptor with PSB36 (2.8 angstrom resolution), caffeine (2.1 angstrom), and theophylline (2.0 angstrom) to highlight features of ligand recognition which are common across xanthines. The structures of A(1)R and A(2A)R were analyzed to identify the differences that are important selectivity determinants for xanthine ligands, and the role of T270(7.35) in A(1)R (M270(7.35) in A(2A)R) in conferring selectivity was confirmed by mutagenesis. The structural differences confirmed to lead to selectivity can be utilized in the design of new subtype-selective A(1)R or A(2A)R antagonists.

引用

页码：1275 / +

页数：15

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