Covalent docking predicts substrates for haloalkanoate dehalogenase superfamily phosphatases

Nir London, Jeremiah D. Farelli, Shoshana D. Brown, Chunliang Liu, Hua Huang, Magdalena Korczynska, Nawar F. Al-Obaidi, Patricia C. Babbitt, Steven C. Almo, Karen N. Allen, Brian K. Shoichet

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Enzyme function prediction remains an important open problem. Though structure-based modeling, such as metabolite docking, can identify substrates of some enzymes, it is ill-suited to reactions that progress through a covalent intermediate. Here we investigated the ability of covalent docking to identify substrates that pass through such a covalent intermediate, focusing particularly on the haloalkanoate dehalogenase superfamily. In retrospective assessments, covalent docking recapitulated substrate binding modes of known cocrystal structures and identified experimental substrates from a set of putative phosphorylated metabolites. In comparison, noncovalent docking of high-energy intermediates yielded nonproductive poses. In prospective predictions against seven enzymes, a substrate was identified for five. For one of those cases, a covalent docking prediction, confirmed by empirical screening, and combined with genomic context analysis, suggested the identity of the enzyme that catalyzes the orphan phosphatase reaction in the riboflavin biosynthetic pathway of Bacteroides.

Original languageEnglish (US)
Pages (from-to)528-537
Number of pages10
JournalBiochemistry
Volume54
Issue number2
DOIs
StatePublished - Jan 20 2015

ASJC Scopus subject areas

  • Biochemistry

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    London, N., Farelli, J. D., Brown, S. D., Liu, C., Huang, H., Korczynska, M., Al-Obaidi, N. F., Babbitt, P. C., Almo, S. C., Allen, K. N., & Shoichet, B. K. (2015). Covalent docking predicts substrates for haloalkanoate dehalogenase superfamily phosphatases. Biochemistry, 54(2), 528-537. https://doi.org/10.1021/bi501140k