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

Journal Article · · FEBS Letters
 [1];  [2];  [3];  [4];  [3];  [2];  [5]
  1. Baylor College of Medicine, Houston, TX (United States). Structural and Computational Biology and Molecular Biophysics Program, Dept. of Chemistry and Chemical Biology
  2. McMaster Univ., Hamilton, ON (Canada). Dept. of Chemistry and Chemical Biology
  3. Univ. of Kassel, Hesse (Germany). Dept. of Biochemistry
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Berkeley Center for Structural Biology
  5. Baylor College of Medicine, Houston, TX (United States). Structural and Computational Biology and Molecular Biophysics Program, Dept. of Chemistry and Chemical Biology, Verna and Marrs McLean Dept. of Biochemistry and Molecular Biology
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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. 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. Our results suggest that Rp-cGMPS inhibits PKG I by stabilizing the inactive conformation of CNB-B.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Institutes of Health (NIH)
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1415962
Journal Information:
FEBS Letters, Journal Name: FEBS Letters Journal Issue: 1 Vol. 591; ISSN 0014-5793
Publisher:
Federation of European Biochemical SocietiesCopyright Statement
Country of Publication:
United States
Language:
English

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