Prediction and assignment of function for a divergent N-succinyl amino acid racemase

Ling Song, Chakrapani Kalyanaraman, Alexander A. Fedorov, Elena V. Fedorov, Margaret E. Glasner, Shoshana Brown, Heidi J. Imker, Patricia C. Babbitt, Steven C. Almo, Matthew P. Jacobson, John A. Gerlt

Research output: Contribution to journalArticle

80 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)486-491
Number of pages6
JournalNature Chemical Biology
Volume3
Issue number8
DOIs
StatePublished - Aug 2007

Fingerprint

Amino Acid Isomerases
Proteins
Ligands
Racemases and Epimerases
Protein Databases
Phosphopyruvate Hydratase
Enzyme Assays
Computer Simulation
Libraries
Arginine

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Song, L., Kalyanaraman, C., Fedorov, A. A., Fedorov, E. V., Glasner, M. E., Brown, S., ... Gerlt, J. A. (2007). Prediction and assignment of function for a divergent N-succinyl amino acid racemase. Nature Chemical Biology, 3(8), 486-491. https://doi.org/10.1038/nchembio.2007.11

Prediction and assignment of function for a divergent N-succinyl amino acid racemase. / Song, Ling; Kalyanaraman, Chakrapani; Fedorov, Alexander A.; Fedorov, Elena V.; Glasner, Margaret E.; Brown, Shoshana; Imker, Heidi J.; Babbitt, Patricia C.; Almo, Steven C.; Jacobson, Matthew P.; Gerlt, John A.

In: Nature Chemical Biology, Vol. 3, No. 8, 08.2007, p. 486-491.

Research output: Contribution to journalArticle

Song, L, Kalyanaraman, C, Fedorov, AA, Fedorov, EV, Glasner, ME, Brown, S, Imker, HJ, Babbitt, PC, Almo, SC, Jacobson, MP & Gerlt, JA 2007, 'Prediction and assignment of function for a divergent N-succinyl amino acid racemase', Nature Chemical Biology, vol. 3, no. 8, pp. 486-491. https://doi.org/10.1038/nchembio.2007.11
Song L, Kalyanaraman C, Fedorov AA, Fedorov EV, Glasner ME, Brown S et al. Prediction and assignment of function for a divergent N-succinyl amino acid racemase. Nature Chemical Biology. 2007 Aug;3(8):486-491. https://doi.org/10.1038/nchembio.2007.11
Song, Ling ; Kalyanaraman, Chakrapani ; Fedorov, Alexander A. ; Fedorov, Elena V. ; Glasner, Margaret E. ; Brown, Shoshana ; Imker, Heidi J. ; Babbitt, Patricia C. ; Almo, Steven C. ; Jacobson, Matthew P. ; Gerlt, John A. / Prediction and assignment of function for a divergent N-succinyl amino acid racemase. In: Nature Chemical Biology. 2007 ; Vol. 3, No. 8. pp. 486-491.
@article{60fd112fd89a4ef3902d9a4acb4879fa,
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.",
author = "Ling Song and Chakrapani Kalyanaraman and Fedorov, {Alexander A.} and Fedorov, {Elena V.} and Glasner, {Margaret E.} and Shoshana Brown and Imker, {Heidi J.} and Babbitt, {Patricia C.} and Almo, {Steven C.} and Jacobson, {Matthew P.} and Gerlt, {John A.}",
year = "2007",
month = "8",
doi = "10.1038/nchembio.2007.11",
language = "English (US)",
volume = "3",
pages = "486--491",
journal = "Nature Chemical Biology",
issn = "1552-4450",
publisher = "Nature Publishing Group",
number = "8",

}

TY - JOUR

T1 - Prediction and assignment of function for a divergent N-succinyl amino acid racemase

AU - Song, Ling

AU - Kalyanaraman, Chakrapani

AU - Fedorov, Alexander A.

AU - Fedorov, Elena V.

AU - Glasner, Margaret E.

AU - Brown, Shoshana

AU - Imker, Heidi J.

AU - Babbitt, Patricia C.

AU - Almo, Steven C.

AU - Jacobson, Matthew P.

AU - Gerlt, John A.

PY - 2007/8

Y1 - 2007/8

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=34447502162&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34447502162&partnerID=8YFLogxK

U2 - 10.1038/nchembio.2007.11

DO - 10.1038/nchembio.2007.11

M3 - Article

C2 - 17603539

AN - SCOPUS:34447502162

VL - 3

SP - 486

EP - 491

JO - Nature Chemical Biology

JF - Nature Chemical Biology

SN - 1552-4450

IS - 8

ER -