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Title: Prediction and Assignment of Function for a Divergent N-succinyl Amino Acid Racemase

Abstract

The protein databases contain many proteins with unknown function. A computational approach for predicting ligand specificity that requires only the sequence of the unknown protein would be valuable for directing experiment-based assignment of function. We focused on a family of unknown proteins in the mechanistically diverse enolase superfamily and used two approaches to assign function: (i) enzymatic assays using libraries of potential substrates, and (ii) in silico docking of the same libraries using a homology model based on the most similar (35% sequence identity) characterized protein. The results matched closely; an experimentally determined structure confirmed the predicted structure of the substrate-liganded complex. We assigned the N-succinyl arginine/lysine racemase function to the family, correcting the annotation (L-Ala-D/L-Glu epimerase) based on the function of the most similar characterized homolog. These studies establish that ligand docking to a homology model can facilitate functional assignment of unknown proteins by restricting the identities of the possible substrates that must be experimentally tested.

Authors:
; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
930002
Report Number(s):
BNL-80613-2008-JA
TRN: US200822%%1155
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature Chemical Biology; Journal Volume: 3
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; AMINO ACIDS; FUNCTIONS; LIBRARIES; LIGANDS; PROTEINS; SPECIFICITY; SUBSTRATES; national synchrotron light source

Citation Formats

Song,L., Kalyanaraman, C., Fedorov, A., Fedorov, E., Glasner, M., Brown, S., Imker, H., Babbitt, P., Almo, S., and et al. Prediction and Assignment of Function for a Divergent N-succinyl Amino Acid Racemase. United States: N. p., 2007. Web. doi:10.1038/nchembio.2007.11.
Song,L., Kalyanaraman, C., Fedorov, A., Fedorov, E., Glasner, M., Brown, S., Imker, H., Babbitt, P., Almo, S., & et al. Prediction and Assignment of Function for a Divergent N-succinyl Amino Acid Racemase. United States. doi:10.1038/nchembio.2007.11.
Song,L., Kalyanaraman, C., Fedorov, A., Fedorov, E., Glasner, M., Brown, S., Imker, H., Babbitt, P., Almo, S., and et al. Mon . "Prediction and Assignment of Function for a Divergent N-succinyl Amino Acid Racemase". United States. doi:10.1038/nchembio.2007.11.
@article{osti_930002,
title = {Prediction and Assignment of Function for a Divergent N-succinyl Amino Acid Racemase},
author = {Song,L. and Kalyanaraman, C. and Fedorov, A. and Fedorov, E. and Glasner, M. and Brown, S. and Imker, H. and Babbitt, P. and Almo, S. and et al.},
abstractNote = {The protein databases contain many proteins with unknown function. A computational approach for predicting ligand specificity that requires only the sequence of the unknown protein would be valuable for directing experiment-based assignment of function. We focused on a family of unknown proteins in the mechanistically diverse enolase superfamily and used two approaches to assign function: (i) enzymatic assays using libraries of potential substrates, and (ii) in silico docking of the same libraries using a homology model based on the most similar (35% sequence identity) characterized protein. The results matched closely; an experimentally determined structure confirmed the predicted structure of the substrate-liganded complex. We assigned the N-succinyl arginine/lysine racemase function to the family, correcting the annotation (L-Ala-D/L-Glu epimerase) based on the function of the most similar characterized homolog. These studies establish that ligand docking to a homology model can facilitate functional assignment of unknown proteins by restricting the identities of the possible substrates that must be experimentally tested.},
doi = {10.1038/nchembio.2007.11},
journal = {Nature Chemical Biology},
number = ,
volume = 3,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}