Document Detail

A substrate selectivity and inhibitor design lesson from the PDE10-cAMP crystal structure: a computational study.
MedLine Citation:
PMID:  20349929     Owner:  NLM     Status:  MEDLINE    
Phosphodiesterases (PDEs) catalyze the hydrolysis of second messengers cAMP and cGMP in regulating many important cellular signals and have been recognized as important drug targets. Experimentally, a range of specificity/selectivity toward cAMP and cGMP is well-known for the individual PDE families. The study reported here reveals that PDEs might also exhibit selectivity toward conformations of the endogenous substrates cAMP and cGMP. Molecular dynamics simulations and free energy study have been applied to study the binding of the cAMP torsional conformers about the glycosyl bond in PDE10A2. The computational results elucidated that PDE10A2 is energetically more favorable in complex with the syn cAMP conformer (as reported in the crystal structure) and the binding of anti cAMP to PDE10A2 would lead to either a nonreactive configuration or significant perturbation on the catalytic pocket of the enzyme. This experimentally inaccessible information provides important molecular insights for the development of effective PDE10 ligands.
Justin Kai-Chi Lau; Xiao-Bo Li; Yuen-Kit Cheng
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The journal of physical chemistry. B     Volume:  114     ISSN:  1520-5207     ISO Abbreviation:  J Phys Chem B     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-15     Completed Date:  2010-06-29     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101157530     Medline TA:  J Phys Chem B     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5154-60     Citation Subset:  IM    
Department of Chemistry, The Hong Kong Baptist University, Waterloo Road, Kowloon Tong, Kowloon, Hong Kong, China.
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MeSH Terms
Crystallography, X-Ray
Cyclic GMP / chemistry*
Molecular Dynamics Simulation
Phosphodiesterase Inhibitors / chemistry*
Phosphoric Diester Hydrolases / chemistry*,  metabolism
Protein Binding
Protein Conformation
Substrate Specificity
Reg. No./Substance:
0/Phosphodiesterase Inhibitors; 7665-99-8/Cyclic GMP; EC 3.1.4.-/Phosphoric Diester Hydrolases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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