Letter abstract
Nature Chemical Biology 3, 486 - 491 (2007)
Published online: 1 July 2007 | doi:10.1038/nchembio.2007.11
Prediction and assignment of function for a divergent N-succinyl amino acid racemase
Ling Song1, Chakrapani Kalyanaraman2, Alexander A Fedorov3, Elena V Fedorov3, Margaret E Glasner4, Shoshana Brown4, Heidi J Imker1, Patricia C Babbitt2,4,5, Steven C Almo3, Matthew P Jacobson2 & John A Gerlt1
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.
- Departments of Biochemistry and Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
- Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, 600 16th Street, San Francisco, California 94158, USA.
- Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
- Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, 1700 4th Street, San Francisco, California 94158, USA.
- California Institute for Quantitative Biomedical Research, University of California, 1700 4th Street, San Francisco, California 94158, USA.
Correspondence to: John A Gerlt1 e-mail: j-gerlt@uiuc.edu
Correspondence to: Matthew P Jacobson2 e-mail: matt.jacobson@ucsf.edu
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