6S73

Crystal structure of Nek7 SRS mutant bound to compound 51

「6GT1」から置き換えられました

6S73 の概要

• エントリーDOI: 10.2210/pdb6s73/pdb
• 関連するPDBエントリー: 6S73 6S76
• 分子名称: Serine/threonine-protein kinase Nek7, 3-[[6-(cyclohexylmethoxy)-7~{H}-purin-2-yl]amino]-~{N}-[3-(dimethylamino)propyl]benzenesulfonamide (2 entities in total)
• 機能のキーワード: kinase, mutant, inhibitor, cell cycle
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 144315.32

構造登録者

Nasir, N.,Byrne, M.J.,Bhatia, C.,Bayliss, R. (登録日: 2019-07-04, 公開日: 2020-06-10, 最終更新日: 2024-01-24)

主引用文献

Byrne, M.J.,Nasir, N.,Basmadjian, C.,Bhatia, C.,Cunnison, R.F.,Carr, K.H.,Mas-Droux, C.,Yeoh, S.,Cano, C.,Bayliss, R.
Nek7 conformational flexibility and inhibitor binding probed through protein engineering of the R-spine.
Biochem.J., 477:1525-1539, 2020

PubMed Abstract: Nek7 is a serine/threonine-protein kinase required for proper spindle formation and cytokinesis. Elevated Nek7 levels have been observed in several cancers, and inhibition of Nek7 might provide a route to the development of cancer therapeutics. To date, no selective and potent Nek7 inhibitors have been identified. Nek7 crystal structures exhibit an improperly formed regulatory-spine (R-spine), characteristic of an inactive kinase. We reasoned that the preference of Nek7 to crystallise in this inactive conformation might hinder attempts to capture Nek7 in complex with Type I inhibitors. Here, we have introduced aromatic residues into the R-spine of Nek7 with the aim to stabilise the active conformation of the kinase through R-spine stacking. The strong R-spine mutant Nek7SRS retained catalytic activity and was crystallised in complex with compound 51, an ATP-competitive inhibitor of Nek2 and Nek7. Subsequently, we obtained the same crystal form for wild-type Nek7WT in apo form and bound to compound 51. The R-spines of the three well-ordered Nek7WT molecules exhibit variable conformations while the R-spines of the Nek7SRS molecules all have the same, partially stacked configuration. Compound 51 bound to Nek2 and Nek7 in similar modes, but differences in the precise orientation of a substituent highlights features that could be exploited in designing inhibitors that are selective for particular Nek family members. Although the SRS mutations are not required to obtain a Nek7-inhibitor structure, we conclude that it is a useful strategy for restraining the conformation of a kinase in order to promote crystallogenesis.

PubMed: 32242624
DOI: 10.1042/BCJ20200128

実験手法

X-RAY DIFFRACTION (3.5 Å)