Crystal structure of cGMP‐dependent protein kinase Iβ cyclic nucleotide‐binding‐B domain : Rp‐cGMPS complex reveals an apo‐like, inactive conformation. Issue 1 (23rd December 2016)

• Record Type: Journal Article
• Authors: Campbell, James C.; VanSchouwen, Bryan; Lorenz, Robin; Sankaran, Banumathi; Herberg, Friedrich W.; Melacini, Giuseppe; Kim, Choel
• Is Part Of: FEBS letters. Volume 591:Issue 1(2017)
• Page Start: 221
• Page End: 230
• Publication Date: 2016-12-23
• Subjects: cGMP‐dependent protein kinase -- kinase inhibition -- NO‐cGMP signaling -- second messengers; Biochemistry -- Periodicals; Biophysics -- Periodicals; Molecular biology -- Periodicals; Biochimie -- Périodiques; Biochemistry; Biophysics; Molecular biology; Periodicals; 572.05
• DOI: 10.1002/1873-3468.12505
• Languages: English
• ISSNs: 0014-5793

Abstract

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 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 its helical domain in an open conformation. Comparison with the cAMP‐dependent protein kinase regulatory subunit (PKA RIα) showed that this conformation resembles the catalytic subunit‐bound inhibited state of PKA RIα 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. Abstract :