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

Gilbert Y. Huang | Zendy; Oksana Gerlits | Zendy; Matthew P. Blakeley | Zendy; Banumathi Sankaran | Zendy; Andrey Kovalevsky | Zendy; Choel Kim | Zendy

Open Access

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

Author(s) -

Gilbert Y. Huang,

Oksana Gerlits,

Matthew P. Blakeley,

Banumathi Sankaran,

Andrey Kovalevsky,

Choel Kim

Publication year - 2014

Publication title -

biochemistry

Language(s) - English

Resource type - Journals

eISSN - 1520-4995

pISSN - 0006-2960

DOI - 10.1021/bi501012v

Subject(s) - cgmp dependent protein kinase , selectivity , protein kinase a , chemistry , agonist , cyclic nucleotide , hydrogen bond , neutron diffraction , cyclic nucleotide gated ion channel , biophysics , kinase , receptor , crystallography , nucleotide , crystal structure , mitogen activated protein kinase kinase , biology , biochemistry , molecule , gene , organic chemistry , catalysis

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). 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.

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