Abstract
Background Cyclic guanosine monophosphate (cGMP) is a key secondary messenger that is produced in response to nitric oxide. One of the key mediators of cGMP signaling, cGMPdependent protein kinase (PKG), is activated upon binding to cGMP and phosphorylates downstream substrates in a process required for important physiological processes such as vasodilation, nociception, and memory formation. PKGs are also known to mediate most effects of drugs that increase cellular cGMP levels, including nitric oxidereleasing agents and phosphodiesterase inhibitors, which are used for the treatment of angina pectoris and erectile dysfunction, respectively. It is known that PKG is preferentially activated by cGMP over cAMP roughly 60-100 fold – however, the molecular mechanism by which cGMP is distinguished from a structurally similar messenger, cAMP, is poorly defined. Using competition fluorescence polarization (FP), X-ray crystallography, and in vitro kinase assays, we sought to understand the molecular basis for cGMP selectivity in PKGI.
Highlights
Cyclic guanosine monophosphate is a key secondary messenger that is produced in response to nitric oxide
Using competition fluorescence polarization (FP), X-ray crystallography, and in vitro kinase assays, we sought to understand the molecular basis for Cyclic guanosine monophosphate (cGMP) selectivity in PKGI
Using X-ray crystallography, we solved the structures of CNB-B bound to cGMP (1.65 Å) and in the apo form (2.0Å)
Summary
Gilbert Y Huang, Jeong J Kim, Albert S Reger, Robin Lorenz, Eui-Whan Moon, Chi Zhao, Darren E Casteel, Daniela Bertinetti, Bryan VanSchouwen, Rajeevan Selvaratnam, James W Pflugrath, Banumathi Sankaran, Giuseppe Melacini, Friedrich W Herberg, Choel Kim1,2*. From 6th International Conference on cGMP: Generators, Effectors and Therapeutic Implications Erfurt, Germany. From 6th International Conference on cGMP: Generators, Effectors and Therapeutic Implications Erfurt, Germany. 28-30 June 2013
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