%0 Journal Article %1 huang2013structural %A Huang, G. %A Kim, J. J. %A Reger, A. %A Lorenz, R. %A Moon, E. %A Zhao, C. %A Casteel, D. E. %A Bertinetti, D. %A VanSchouwen, B. %A Selvaratnam, R. %A Pflugrath, J. W. %A Sankaran, B. %A Melacini, G. %A Herberg, F. W. %A Kim, C. %D 2014 %I Cell Press %J Structure %K herberg myown %N 1 %P 116-24 %R 10.1016/j.str.2013.09.021 %T Structural Basis for Cyclic-Nucleotide Selectivity and cGMP-Selective Activation of PKG I %U http://www.ncbi.nlm.nih.gov/pubmed/24239458 %V 22 %X Cyclic guanosine monophosphate (cGMP) and cyclic AMP (cAMP)-dependent protein kinases (PKG and PKA) are closely related homologs, and the cyclic nucleotide specificity of each kinase is crucial for keeping the two signaling pathways segregated, but the molecular mechanism of cyclic nucleotide selectivity is unknown. Here, we report that the PKG I� C-terminal cyclic nucleotide binding domain (CNB-B) is highly selective for cGMP binding, and we have solved crystal structures of CNB-B with and without bound cGMP. These structures, combined with a comprehensive mutagenic analysis, allowed us to identify Leu296 and Arg297 as key residues that mediate cGMP selectivity. In addition, by comparing the cGMP bound and unbound structures, we observed large conformational changes in the C-terminal helices in response to cGMP binding, which were stabilized by recruitment of Tyr351 as a�capping residue for cGMP. The observed rearrangements of the C-terminal helices provide a mechanical insight into release of the catalytic domain and kinase activation. "Structural analysis reveals contacts required for cGMP selectivity"Mutagenesis of these residues impairs cGMP-selective binding and activation"Crystal structures describe conformational changes required for kinase activation PKG is activated by the second messenger cGMP and regulates vasodilation. The mechanism by which PKG specifically responds to cGMP, and not cAMP, is poorly understood. Huang et�al. now provide structure-based insight into cGMP selectivity of PKG and conformational changes required for kinase activation.

@article{huang2013structural, abstract = {Cyclic guanosine monophosphate (cGMP) and cyclic AMP (cAMP)-dependent protein kinases (PKG and PKA) are closely related homologs, and the cyclic nucleotide specificity of each kinase is crucial for keeping the two signaling pathways segregated, but the molecular mechanism of cyclic nucleotide selectivity is unknown. Here, we report that the PKG I� C-terminal cyclic nucleotide binding domain (CNB-B) is highly selective for cGMP binding, and we have solved crystal structures of CNB-B with and without bound cGMP. These structures, combined with a comprehensive mutagenic analysis, allowed us to identify Leu296 and Arg297 as key residues that mediate cGMP selectivity. In addition, by comparing the cGMP bound and unbound structures, we observed large conformational changes in the C-terminal helices in response to cGMP binding, which were stabilized by recruitment of Tyr351 as a�capping residue for cGMP. The observed rearrangements of the C-terminal helices provide a mechanical insight into release of the catalytic domain and kinase activation. "Structural analysis reveals contacts required for cGMP selectivity"Mutagenesis of these residues impairs cGMP-selective binding and activation"Crystal structures describe conformational changes required for kinase activation PKG is activated by the second messenger cGMP and regulates vasodilation. The mechanism by which PKG specifically responds to cGMP, and not cAMP, is poorly understood. Huang et�al. now provide structure-based insight into cGMP selectivity of PKG and conformational changes required for kinase activation.}, added-at = {2013-11-14T18:05:43.000+0100}, author = {Huang, G. and Kim, J. J. and Reger, A. and Lorenz, R. and Moon, E. and Zhao, C. and Casteel, D. E. and Bertinetti, D. and VanSchouwen, B. and Selvaratnam, R. and Pflugrath, J. W. and Sankaran, B. and Melacini, G. and Herberg, F. W. and Kim, C.}, biburl = {https://www.bibsonomy.org/bibtex/200ba6934ae597fd08e0d6a8a96b10613/biochemie}, description = {Structure - Structural Basis for Cyclic-Nucleotide Selectivity and cGMP-Selective Activation of PKG I}, doi = {10.1016/j.str.2013.09.021}, interhash = {55527df0d02b46245bb268e6e76fa879}, intrahash = {00ba6934ae597fd08e0d6a8a96b10613}, issn = {09692126}, journal = {Structure}, keywords = {herberg myown}, number = 1, pages = {116-24}, publisher = {Cell Press}, refid = {S0969-2126(13)00394-8 DOI - 10.1016/j.str.2013.09.021}, timestamp = {2014-01-14T10:46:02.000+0100}, title = {Structural Basis for Cyclic-Nucleotide Selectivity and cGMP-Selective Activation of PKG I}, url = {http://www.ncbi.nlm.nih.gov/pubmed/24239458}, volume = 22, year = 2014 }