title: Thymoquinone blocks pSer/pThr recognition by Plk1 Polo-box domain as a phosphate mimic.
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.
authors.affiliation: School of Life Science and Technology, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, Jiangsu 210009, China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Yin
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Song
authors.forename: Peter H
authors.initials: PH
authors.lastname: Rehse
mesh_terms: D016227:Benzoquinones / Q000737:chemistry* / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D010710:Phosphates / Q000737:chemistry*; D010766:Phosphorylation; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013912:Threonine / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
chemical_list: D016227:Benzoquinones; D018797:Cell Cycle Proteins; D010710:Phosphates; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D012694:Serine; D013912:Threonine; D000097869:Polo-Like Kinase 1; C003466:thymoquinone