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Title: Conformation changes, N-terminal involvement and cGMP signal relay in phosphodiesterase-5 GAF domain

Abstract

The activity of phosphodiesterase-5 (PDE5) is specific for cGMP and is regulated by cGMP binding to GAF-A in its regulatory domain. To better understand the regulatory mechanism, x-ray crystallographic and biochemical studies were performed on constructs of human PDE5A1 containing the N-terminal phosphorylation segment, GAF-A, and GAF-B. Superposition of this unliganded GAF-A with the previously reported NMR structure of cGMP-bound PDE5 revealed dramatic conformational differences and suggested that helix H4 and strand B3 probably serve as two lids to gate the cGMP-binding pocket in GAF-A. The structure also identified an interfacial region among GAF-A, GAF-B, and the N-terminal loop, which may serve as a relay of the cGMP signal from GAF-A to GAF-B. N-terminal loop 98-147 was physically associated with GAF-B domains of the dimer. Biochemical analyses showed an inhibitory effect of this loop on cGMP binding and its involvement in the cGMP-induced conformation changes.

Authors:
; ;
Publication Date:
Research Org.:
Brookhaven National Lab. (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE SC OFFICE OF SCIENCE (SC)
OSTI Identifier:
1040560
Report Number(s):
BNL-94517-2011-JA
Journal ID: ISSN 0021-9258; JBCHA3; R&D Project: BO-070; KP1605010; TRN: US201210%%736
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Journal Name:
Journal of Biological Chemistry
Additional Journal Information:
Journal Volume: 285; Journal Issue: 49; Journal ID: ISSN 0021-9258
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; CRYSTAL STRUCTURE; NUCLEOTIDES; PHOSPHODIESTERASES; PHOSPHORYLATION

Citation Formats

Wang, H, Robinson, H, and Ke, H. Conformation changes, N-terminal involvement and cGMP signal relay in phosphodiesterase-5 GAF domain. United States: N. p., 2010. Web. doi:10.1074/jbc.M110.141614.
Wang, H, Robinson, H, & Ke, H. Conformation changes, N-terminal involvement and cGMP signal relay in phosphodiesterase-5 GAF domain. United States. https://doi.org/10.1074/jbc.M110.141614
Wang, H, Robinson, H, and Ke, H. 2010. "Conformation changes, N-terminal involvement and cGMP signal relay in phosphodiesterase-5 GAF domain". United States. https://doi.org/10.1074/jbc.M110.141614.
@article{osti_1040560,
title = {Conformation changes, N-terminal involvement and cGMP signal relay in phosphodiesterase-5 GAF domain},
author = {Wang, H and Robinson, H and Ke, H},
abstractNote = {The activity of phosphodiesterase-5 (PDE5) is specific for cGMP and is regulated by cGMP binding to GAF-A in its regulatory domain. To better understand the regulatory mechanism, x-ray crystallographic and biochemical studies were performed on constructs of human PDE5A1 containing the N-terminal phosphorylation segment, GAF-A, and GAF-B. Superposition of this unliganded GAF-A with the previously reported NMR structure of cGMP-bound PDE5 revealed dramatic conformational differences and suggested that helix H4 and strand B3 probably serve as two lids to gate the cGMP-binding pocket in GAF-A. The structure also identified an interfacial region among GAF-A, GAF-B, and the N-terminal loop, which may serve as a relay of the cGMP signal from GAF-A to GAF-B. N-terminal loop 98-147 was physically associated with GAF-B domains of the dimer. Biochemical analyses showed an inhibitory effect of this loop on cGMP binding and its involvement in the cGMP-induced conformation changes.},
doi = {10.1074/jbc.M110.141614},
url = {https://www.osti.gov/biblio/1040560}, journal = {Journal of Biological Chemistry},
issn = {0021-9258},
number = 49,
volume = 285,
place = {United States},
year = {Fri Dec 03 00:00:00 EST 2010},
month = {Fri Dec 03 00:00:00 EST 2010}
}