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

15 Citations (Scopus)

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

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Phosphoric Monoester Hydrolases
Substrates
Enzymes
Metabolites
Bacteroides
Riboflavin
Biosynthetic Pathways
Screening

ASJC Scopus subject areas

  • Biochemistry

Cite this

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

Covalent docking predicts substrates for haloalkanoate dehalogenase superfamily phosphatases. / London, Nir; Farelli, Jeremiah D.; Brown, Shoshana D.; Liu, Chunliang; Huang, Hua; Korczynska, Magdalena; Al-Obaidi, Nawar F.; Babbitt, Patricia C.; Almo, Steven C.; Allen, Karen N.; Shoichet, Brian K.

In: Biochemistry, Vol. 54, No. 2, 20.01.2015, p. 528-537.

Research output: Contribution to journalArticle

London, N, Farelli, JD, Brown, SD, Liu, C, Huang, H, Korczynska, M, Al-Obaidi, NF, Babbitt, PC, Almo, SC, Allen, KN & Shoichet, BK 2015, 'Covalent docking predicts substrates for haloalkanoate dehalogenase superfamily phosphatases', Biochemistry, vol. 54, no. 2, pp. 528-537. https://doi.org/10.1021/bi501140k
London N, Farelli JD, Brown SD, Liu C, Huang H, Korczynska M et al. Covalent docking predicts substrates for haloalkanoate dehalogenase superfamily phosphatases. Biochemistry. 2015 Jan 20;54(2):528-537. https://doi.org/10.1021/bi501140k
London, Nir ; Farelli, Jeremiah D. ; Brown, Shoshana D. ; Liu, Chunliang ; Huang, Hua ; Korczynska, Magdalena ; Al-Obaidi, Nawar F. ; Babbitt, Patricia C. ; Almo, Steven C. ; Allen, Karen N. ; Shoichet, Brian K. / Covalent docking predicts substrates for haloalkanoate dehalogenase superfamily phosphatases. In: Biochemistry. 2015 ; Vol. 54, No. 2. pp. 528-537.
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