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 language | English (US) |
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Pages (from-to) | 303-308 |
Number of pages | 6 |
Journal | ACS Chemical Biology |
Volume | 8 |
Issue number | 2 |
DOIs | |
State | Published - Feb 15 2013 |
Externally published | Yes |
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine