The crystal structures of PKG Iβ (92-227) with cGMP and cAMP reveal the molecular details of cyclic-nucleotide binding

Cyclic GMP is a crucial second messenger that translates extracellular signals into a variety of cellular responses. As a central mediator of the Nitric Oxide-cGMP signalling cascade, which regulates vascular tone, platelet aggregation, nociception and hipocampal/cerebellar learning, Cyclic GMP-dependent protein kinases (PKGs) represents an important drug target for treating hypertensive diseases and erectile dysfunction. The fidelity of the NO-cGMP signaling pathway is largely dependent on PKG’s ability to selectively bind cGMP over cAMP. Although both cGMP and cAMP bind and activate PKG, cGMP preferentially activates PKG 60-100 fold better than cAMP; yet, little is known about the molecular features required for the cGMP selectivity of PKG. We have investigated the mechanism of cyclic nucleotide binding to PKG by determining crystal structures of the amino-terminal cyclic nucleotide-binding domain (CNBD-A) of human PKG I bound to either cGMP or cAMP. We also determined the structure of CNBD-A in the absence of bound nucleotide.