Journal article
Crystal structure of PKG Iß CNB-B:Rp-cGMPS complex reveals an apo-like, inactive conformation
Publication Details
Authors: | Campbell, J.; VanSchouwen, B.; Lorenz, R.; Sankaran, B.; Herberg, F.; Melacini, G.; Kim, C. |
Publishing status: | In press / published online in advance |
ISSN: | 0014-5793 |
eISSN: | 1873-3468 |
DOI-Link der Erstveröffentlichung: |
URN / URL: |
Abstract
The R-enantiomer 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 Iß cyclic nucleotide-binding domain (PKG Iß CNB-B), considered a 'gatekeeper' for cGMP activation, bound to Rp-cGMPS at 1.3 Å. Our structural and NMR data show that PKG Iß 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 RIa) showed that this conformation resembles the catalytic subunit-bound inhibited state of PKA RIa 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.This article is protected by copyright. All rights reserved.
The R-enantiomer 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 Iß cyclic nucleotide-binding domain (PKG Iß CNB-B), considered a 'gatekeeper' for cGMP activation, bound to Rp-cGMPS at 1.3 Å. Our structural and NMR data show that PKG Iß 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 RIa) showed that this conformation resembles the catalytic subunit-bound inhibited state of PKA RIa 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.This article is protected by copyright. All rights reserved.
