Martinez Sergio E, Beavo Joseph A, Hol Wim G J
Department of Pharmacology, University of Washington, Seattle, WA 98195-7280, USA.
Mol Interv. 2002 Sep;2(5):317-23. doi: 10.1124/mi.2.5.317.
GAF domains represent one of the largest families of small-molecule binding units present in nature. The first mammalian GAF domains discovered were the cGMP-binding regulatory domains of several cyclic nucleotide phosphodiesterases (PDEs). The crystal structure of the PDE2A GAF domains has provided our first look at the architecture of the binding site for the second messenger cGMP. The topology of this site differs greatly from all other previously determined cyclic nucleotide binding sites. In PDE2A, cGMP binds to a well-defined pocket in one of the two GAF domains that is analogous to the ligand-binding pocket of the distantly related PAS domains of photoactive yellow protein and FixL. The consensus cGMP-binding motif suggests strongly that only certain GAF domains will bind cGMP. Although the detailed mechanism for how cGMP binding to the GAF domain regulates catalysis remains to be determined, recent data from a GAF domain-containing cAMP-stimulated adenylyl cyclase from Anabaena suggest a mechanism conserved across two billion years of evolution. Because of their unique ligand-binding topologies, the GAF domains of PDEs are likely to offer good new targets for rational drug design.
GAF结构域是自然界中存在的最大的小分子结合单元家族之一。最早发现的哺乳动物GAF结构域是几种环核苷酸磷酸二酯酶（PDEs）的cGMP结合调节结构域。PDE2A GAF结构域的晶体结构让我们首次了解了第二信使cGMP结合位点的结构。该位点的拓扑结构与之前确定的所有其他环核苷酸结合位点有很大不同。在PDE2A中，cGMP结合到两个GAF结构域之一中一个明确的口袋中，该口袋类似于光活性黄色蛋白和FixL的远亲PAS结构域的配体结合口袋。cGMP结合基序强烈表明只有某些GAF结构域会结合cGMP。尽管cGMP与GAF结构域结合如何调节催化的详细机制仍有待确定，但来自鱼腥藻的含GAF结构域的cAMP刺激的腺苷酸环化酶的最新数据表明了一种在二十亿年进化过程中保守的机制。由于其独特的配体结合拓扑结构，PDEs的GAF结构域可能为合理药物设计提供良好的新靶点。
