skip to main content

DOE PAGESDOE PAGES

Title: Neutron diffraction reveals hydrogen bonds critical for cGMP-selective activation: Insights for cGMP-dependent protein kinase agonist design

High selectivity of cyclic-nucleotide binding (CNB) domains for cAMP and cGMP are required for segregating signaling pathways; however, the mechanism of selectivity remains unclear. To investigate the mechanism of high selectivity in cGMP-dependent protein kinase (PKG), we determined a room-temperature joint X-ray/neutron (XN) structure of PKG Iβ CNB-B, a domain 200-fold selective for cGMP over cAMP, bound to cGMP (2.2 Å), and a low-temperature X-ray structure of CNB-B with cAMP (1.3 Å). Finally, the XN structure directly describes the hydrogen bonding interactions that modulate high selectivity for cGMP, while the structure with cAMP reveals that all these contacts are disrupted, explaining its low affinity for cAMP.
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [2] ;  [1]
  1. Baylor College of Medicine, Houston, TX (United States)
  2. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
  3. Institute Laue-Langevin, Grenoble (France)
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Publication Date:
Grant/Contract Number:
AC02-05CH11231; R01GM90161
Type:
Published Article
Journal Name:
Biochemistry
Additional Journal Information:
Journal Volume: 53; Journal Issue: 43; Journal ID: ISSN 0006-2960
Publisher:
American Chemical Society (ACS)
Research Org:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES
OSTI Identifier:
1163250
Alternate Identifier(s):
OSTI ID: 1257634