Thymoquinone blocks pSer/pThr recognition by plk1 polo-box domain as a phosohate mimic

Zhou Yin, Yunlong Song, Peter H. Rehse

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Phosphorylation-dependent protein-protein interaction has rarely been targeted in medicinal chemistry. Thymoquinone, a naturally occurring antitumor agent, disrupts prephosphorylated substrate recognition by the polo-box domain of polo-like kinase 1, a key mitotic regulator responsible for various carcinogenesis when overexpressed. Here, crystallographic studies reveal that the phosphoserine/phosphothreonine recognition site of the polo-box domain is the binding pocket for thymoquinone and its analogue poloxime. Both small molecules displace phosphopeptides bound with the polo-box domain in a slow but noncovalent binding mode. A conserved water bridge and a cation-π interaction were found as their competition strategy against the phosphate group. This mechanism sheds light on small-molecule intervention of phospho-recognition by the polo-box domain of polo-like kinase 1 and other phospho-binding proteins in general.

Original languageEnglish (US)
Pages (from-to)303-308
Number of pages6
JournalACS Chemical Biology
Volume8
Issue number2
DOIs
StatePublished - Feb 15 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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