Document Detail


Capture and quality control mechanisms for adenosine-5'-triphosphate binding.
MedLine Citation:
PMID:  23276298     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The catalytic events in members of the nucleotidylyl transferase superfamily are initiated by a millisecond binding of ATP in the active site. Through metadynamics simulations on a class I aminoacyl-tRNA synthetase (aaRSs), the largest group in the superfamily, we calculate the free energy landscape of ATP selection and binding. Mutagenesis studies and fluorescence spectroscopy validated the identification of the most populated intermediate states. The rapid first binding step involves formation of encounter complexes captured through a fly casting mechanism that acts upon the triphosphate moiety of ATP. In the slower nucleoside binding step, a conserved histidine in the HxxH motif orients the incoming ATP through base-stacking interactions resulting in a deep minimum in the free energy surface. Mutation of this histidine significantly decreases the binding affinity measured experimentally and computationally. The metadynamics simulations further reveal an intermediate quality control state that the synthetases and most likely other members of the superfamily use to select ATP over other nucleoside triphosphates.
Authors:
Li Li; Susan A Martinis; Zaida Luthey-Schulten
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2013-02-13
Journal Detail:
Title:  Journal of the American Chemical Society     Volume:  135     ISSN:  1520-5126     ISO Abbreviation:  J. Am. Chem. Soc.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-04-24     Completed Date:  2013-11-07     Revised Date:  2014-04-25    
Medline Journal Info:
Nlm Unique ID:  7503056     Medline TA:  J Am Chem Soc     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6047-55     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / chemistry*,  metabolism*
Algorithms
Amino Acyl-tRNA Synthetases / chemistry
Catalysis
Cloning, Molecular
Computer Simulation
Fluorescent Dyes
Histidine / chemistry,  genetics
Magnetic Resonance Spectroscopy
Models, Molecular
Molecular Conformation
Mutagenesis
Mutation / genetics
Nucleosides / chemistry
Spectrometry, Fluorescence
Thermus thermophilus / enzymology,  genetics
Grant Support
ID/Acronym/Agency:
GM 063789/GM/NIGMS NIH HHS; P41 RR005969/RR/NCRR NIH HHS; P41 RR05969/RR/NCRR NIH HHS; R01 GM063789/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Fluorescent Dyes; 0/Nucleosides; 4QD397987E/Histidine; 8L70Q75FXE/Adenosine Triphosphate; EC 6.1.1.-/Amino Acyl-tRNA Synthetases
Comments/Corrections

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


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