Summary for 6SK9
| Entry DOI | 10.2210/pdb6sk9/pdb |
| Descriptor | Serine/threonine-protein kinase Nek2, 3-[[6-(cyclohexylmethoxy)-7~{H}-purin-2-yl]amino]-~{N}-[3-(dimethylamino)propyl]benzenesulfonamide, GLYCEROL, ... (4 entities in total) |
| Functional Keywords | ser/thr protein kinase, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 33242.19 |
| Authors | Bayliss, R.,Byrne, M.J.,Mas-Droux, C. (deposition date: 2019-08-15, release date: 2020-06-17, Last modification date: 2024-05-15) |
| Primary citation | 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 Cited by 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: 32242624DOI: 10.1042/BCJ20200128 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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