RIS ID
75850
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.
Publication Details
Yin, Z., Song, Y. & Rehse, P. H. (2013). Thymoquinone blocks pSer/pThr recognition by plk1 polo-box domain as a phosohate mimic. ACS Chemical Biology, 8 (2), 303-308.