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Crystal structure of cGMP-dependent protein kinase I? cyclic nucleotide-binding-B domain : Rp-cGMPS complex reveals an apo-like, inactive conformation.

ABSTRACT: The R-diastereomer of phosphorothioate analogs of cGMP, Rp-cGMPS, is one of few known inhibitors of cGMP-dependent protein kinase I (PKG I); however, its mechanism of inhibition is currently not fully understood. Here, we determined the crystal structure of the PKG I? cyclic nucleotide-binding domain (PKG I? CNB-B), considered a 'gatekeeper' for cGMP activation, bound to Rp-cGMPS at 1.3 Å. Our structural and NMR data show that PKG I? CNB-B bound to Rp-cGMPS displays an apo-like structure with its helical domain in an open conformation. Comparison with the cAMP-dependent protein kinase regulatory subunit (PKA RI?) showed that this conformation resembles the catalytic subunit-bound inhibited state of PKA RI? more closely than the apo or Rp-cAMPS-bound conformations. These results suggest that Rp-cGMPS inhibits PKG I by stabilizing the inactive conformation of CNB-B.

SUBMITTER: Campbell JC 

PROVIDER: S-EPMC5407887 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Crystal structure of cGMP-dependent protein kinase Iβ cyclic nucleotide-binding-B domain : Rp-cGMPS complex reveals an apo-like, inactive conformation.

Campbell James C JC   VanSchouwen Bryan B   Lorenz Robin R   Sankaran Banumathi B   Herberg Friedrich W FW   Melacini Giuseppe G   Kim Choel C  

FEBS letters 20161223 1

The R-diastereomer of phosphorothioate analogs of cGMP, Rp-cGMPS, is one of few known inhibitors of cGMP-dependent protein kinase I (PKG I); however, its mechanism of inhibition is currently not fully understood. Here, we determined the crystal structure of the PKG Iβ cyclic nucleotide-binding domain (PKG Iβ CNB-B), considered a 'gatekeeper' for cGMP activation, bound to Rp-cGMPS at 1.3 Å. Our structural and NMR data show that PKG Iβ CNB-B bound to Rp-cGMPS displays an apo-like structure with it  ...[more]

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