MOLECULAR MODELING OF ADENOSINE RECEPTORS - THE LIGAND-BINDING SITE ON THE RAT ADENOSINE A(2A) RECEPTOR

被引：43

作者：

IJZERMAN, AP ^{[1
]}

VANDERWENDEN, EM ^{[1
]}

VANGALEN, PJM ^{[1
]}

JACOBSON, KA ^{[1
]}

机构：

[1] NIDDK, BIOORGAN CHEM LAB, BETHESDA, MD 20892 USA

来源：

EUROPEAN JOURNAL OF PHARMACOLOGY-MOLECULAR PHARMACOLOGY SECTION | 1994年 / 268卷 / 01期

关键词：

MOLECULAR MODELING; ADENOSINE RECEPTOR; RECEPTOR BINDING AND ACTIVATION; BACTERIORHODOPSIN; HISTIDINE RESIDUE;

D O I：

10.1016/0922-4106(94)90124-4

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The amino acid sequence of the rat adenosine A(2A) receptor and the atomic coordinates of bacteriorhodopsin were combined to generate a three-dimensional model for the adenosine A(2A) receptor. This model consists of seven amphipathic alpha-helices, forming a pore that is rather hydrophilic compared to the hydrophobic outside of the protein. Subsequently, a highly potent and selective ligand for this receptor, 2-(cyclohexylmethylidinehydrazino)adenosine (SHA 174), was docked into this cavity. A binding site is proposed that takes into account the conformational characteristics of the ligand. Moreover, it involves two histidine residues that were shown to be important for ligand coordination from chemical modification studies. Subsequently, the deduced binding site was used to model other potent ligands, including 8-(3-chlorostyryl)caffeine, a new A(2)-selective antagonist, that could all be accommodated consistent with earlier biochemical and pharmacological findings. Finally, some thoughts on how adenosine receptor activation might proceed are put forward, based on structural analogies with the enzyme family of serine proteases.

引用

页码：95 / 104

页数：10

共 41 条

[11] THE PREDICTION OF TRANSMEMBRANE PROTEIN SEQUENCES AND THEIR CONFORMATION - AN EVALUATION [J].