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

[Image: see text] 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 determin...

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Autores principales: Huang, Gilbert Y., Gerlits, Oksana O., Blakeley, Matthew P., Sankaran, Banumathi, Kovalevsky, Andrey Y., Kim, Choel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2014
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222537/
https://www.ncbi.nlm.nih.gov/pubmed/25271401
http://dx.doi.org/10.1021/bi501012v
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author Huang, Gilbert Y.
Gerlits, Oksana O.
Blakeley, Matthew P.
Sankaran, Banumathi
Kovalevsky, Andrey Y.
Kim, Choel
author_facet Huang, Gilbert Y.
Gerlits, Oksana O.
Blakeley, Matthew P.
Sankaran, Banumathi
Kovalevsky, Andrey Y.
Kim, Choel
author_sort Huang, Gilbert Y.
collection PubMed
description [Image: see text] 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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spelling pubmed-42225372015-10-01 Neutron Diffraction Reveals Hydrogen Bonds Critical for cGMP-Selective Activation: Insights for cGMP-Dependent Protein Kinase Agonist Design Huang, Gilbert Y. Gerlits, Oksana O. Blakeley, Matthew P. Sankaran, Banumathi Kovalevsky, Andrey Y. Kim, Choel Biochemistry [Image: see text] 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. American Chemical Society 2014-10-01 2014-11-04 /pmc/articles/PMC4222537/ /pubmed/25271401 http://dx.doi.org/10.1021/bi501012v Text en Copyright © 2014 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Huang, Gilbert Y.
Gerlits, Oksana O.
Blakeley, Matthew P.
Sankaran, Banumathi
Kovalevsky, Andrey Y.
Kim, Choel
Neutron Diffraction Reveals Hydrogen Bonds Critical for cGMP-Selective Activation: Insights for cGMP-Dependent Protein Kinase Agonist Design
title Neutron Diffraction Reveals Hydrogen Bonds Critical for cGMP-Selective Activation: Insights for cGMP-Dependent Protein Kinase Agonist Design
title_full Neutron Diffraction Reveals Hydrogen Bonds Critical for cGMP-Selective Activation: Insights for cGMP-Dependent Protein Kinase Agonist Design
title_fullStr Neutron Diffraction Reveals Hydrogen Bonds Critical for cGMP-Selective Activation: Insights for cGMP-Dependent Protein Kinase Agonist Design
title_full_unstemmed Neutron Diffraction Reveals Hydrogen Bonds Critical for cGMP-Selective Activation: Insights for cGMP-Dependent Protein Kinase Agonist Design
title_short Neutron Diffraction Reveals Hydrogen Bonds Critical for cGMP-Selective Activation: Insights for cGMP-Dependent Protein Kinase Agonist Design
title_sort neutron diffraction reveals hydrogen bonds critical for cgmp-selective activation: insights for cgmp-dependent protein kinase agonist design
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4222537/
https://www.ncbi.nlm.nih.gov/pubmed/25271401
http://dx.doi.org/10.1021/bi501012v
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