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Title: Neutron Diffraction Reveals Hydrogen Bonds Critical for cGMP-Selective Activation: Insights for cGMP-Dependent Protein Kinase Agonist Design

Journal Article · · Biochemistry
DOI: https://doi.org/10.1021/bi501012v · OSTI ID:1163250
 [1];  [2];  [3];  [4];  [2];  [5]
  1. Verna and Mars McClean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77004, United States
  2. Biology and Soft Matter Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States
  3. Institute Laue-Langevin, 71 Avenue des Martyrs, 38000, Grenoble, France
  4. Berkeley Center for Structural Biology, Lawrence Berkeley National Laboratory, Berkeley, California, United States
  5. Verna and Mars McClean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77004, United States, Department of Pharmacology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77004, United States

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.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
AC02-05CH11231; R01GM90161
OSTI ID:
1163250
Alternate ID(s):
OSTI ID: 1257634
Journal Information:
Biochemistry, Journal Name: Biochemistry Vol. 53 Journal Issue: 43; ISSN 0006-2960
Publisher:
American Chemical SocietyCopyright Statement
Country of Publication:
United States
Language:
English