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Predicting the open conformations of protein kinases using molecular dynamics simulations.
MedLine Citation:
PMID:  21858778     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Protein kinases (PK) control phosphorylation in eukaryotic cells, and thereby regulate metabolic pathways, cell cycle progression, apoptosis and transcription. Consequently there is significant interest in manipulating PK activity and treat diseases by using small-molecule drugs. All PK catalytic domains undergo large conformational changes as a result of substrate binding and phosphorylation. The "closed" state of a PK cataltic domain is the only state able to phosphorylate the target substrate, which makes the two other observed states (the "open" and the "intermediate" states) interesting drug targets. We investigate if MD simulations starting from the closed state of the catalytic domain of protein kinase A (C-PKA) can be used to produce realistic structures representing the intermediate and/or open conformation of C-PKA, since this would allow for drug docking calculations and drug design using MD snapshots. We perform 36 ten-nanosecond MD simulations starting from the closed conformation (PDB ID: 1ATP) of C-PKA in various liganded and phosphorylated states. The results show that MD simulations are capable of reproducing the open conformation of C-PKA with good accuracy within 1 ns of simulation as measured by Cα RMSDs and RMSDs of atoms defining the ATP-binding pocket. Importantly we are able to show that even without knowledge of the structure of the open form of C-PKA, we can identify the MD snapshots resembling the open conformation most using the open structure of a different protein kinase displaying only 23% sequence identity to C-PKA. © 2011 Wiley Periodicals, Inc. Biopolymers, 2011.
Authors:
Una Bjarnadottir; Jens Erik Nielsen
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-8-19
Journal Detail:
Title:  Biopolymers     Volume:  -     ISSN:  0006-3525     ISO Abbreviation:  -     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-8-22     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0372525     Medline TA:  Biopolymers     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011 Wiley Periodicals, Inc.
Affiliation:
School of Biomolecular and Biomedical Science, Centre for Synthesis and Chemical Biology, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
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