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Determination of the Formylglycinamide Ribonucleotide.Amidotransferase Ammonia Pathway by Combining 3D-RISM Theory with Experiment

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Title Determination of the Formylglycinamide Ribonucleotide.Amidotransferase Ammonia Pathway by Combining 3D-RISM Theory with Experiment
 
Creator TANWAR, AS
SINDHIKARA, DJ
HIRATA, F
ANAND, R
 
Subject CARBAMOYL-PHOSPHATE SYNTHETASE
MOLECULAR-DYNAMICS SIMULATIONS
INTERACTION SITE MODEL
RIBONUCLEOTIDE AMIDOTRANSFERASE
LIQUID WATER
ACTIVE-SITE
SUBSTRATE
GLUTAMINE
DOMAIN
MECHANISM
 
Description Molecular tunnels in enzyme systems possess variable architecture and are therefore difficult to predict. In this work, we design and apply an algorithm to resolve the pathway followed by ammonia using the bifunctional enzyme formylglycinamide ribonucleotide amidotransferase (FGAR-AT) as a model system. Though its crystal structure has been determined, an ammonia pathway connecting the glutaminase domain to the 30 angstrom distal FGAR/ATP binding site remains elusive. Crystallography suggested two purported paths: an N-terminal-adjacent path (path 1) and an auxiliary ADP-adjacent path (path 2). The algorithm presented here, RismPath, which enables fast and accurate determination of solvent distribution inside a protein channel, predicted path 2 as the preferred mode of ammonia transfer. Supporting experimental studies validate the identity of the path, and results lead to the conclusion that the residues in the middle of the channel do not partake in catalytic coupling and serve only as channel walls facilitating ammonia transfer.
 
Publisher AMER CHEMICAL SOC
 
Date 2016-01-15T06:22:03Z
2016-01-15T06:22:03Z
2015
 
Type Article
 
Identifier ACS CHEMICAL BIOLOGY, 10(3)698-704
1554-8929
1554-8937
http://dx.doi.org/10.1021/cb501015r
http://dspace.library.iitb.ac.in/jspui/handle/100/17920
 
Language en