6INL
Crystal structure of CDK2 IN complex with Inhibitor CVT-313
Summary for 6INL
| Entry DOI | 10.2210/pdb6inl/pdb |
| Descriptor | Cyclin-dependent kinase 2, 2,2'-{[6-{[(4-methoxyphenyl)methyl]amino}-9-(propan-2-yl)-9H-purin-2-yl]azanediyl}di(ethan-1-ol) (3 entities in total) |
| Functional Keywords | cyclin dependent kinases, cdks, cell cycle-inhibitor complex, cell cycle/inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 34464.04 |
| Authors | Talapati, S.R.,Krishnamurthy, N.R. (deposition date: 2018-10-25, release date: 2019-10-30, Last modification date: 2023-11-22) |
| Primary citation | Talapati, S.R.,Nataraj, V.,Pothuganti, M.,Gore, S.,Ramachandra, M.,Antony, T.,More, S.S.,Krishnamurthy, N.R. Structure of cyclin-dependent kinase 2 (CDK2) in complex with the specific and potent inhibitor CVT-313. Acta Crystallogr.,Sect.F, 76:350-356, 2020 Cited by PubMed Abstract: CVT-313 is a potent CDK2 inhibitor that was identified by screening a purine-analogue library and is currently in preclinical studies. Since this molecule has the potential to be developed as a CDK2 inhibitor for cancer therapy, the potency of CVT-313 to bind and stabilize CDK2 was evaluated, together with its ability to inhibit aberrant cell proliferation. CVT-313 increased the melting temperature of CDK2 by 7°C in thermal stabilization studies, thus indicating its protein-stabilizing effect. CVT-313 inhibited the growth of human lung carcinoma cell line A549 in a dose-dependent manner, with an IC of 1.2 µM, which is in line with the reported biochemical potency of 0.5 µM. To support the further chemical modification of CVT-313 and to improve its biochemical and cellular potency, a crystal structure was elucidated in order to understand the molecular interaction of CVT-313 and CDK2. The crystal structure of CDK2 bound to CVT-313 was determined to a resolution of 1.74 Å and clearly demonstrated that CVT-313 binds in the ATP-binding pocket, interacting with Leu83, Asp86 and Asp145 directly, and the binding was further stabilized by a water-mediated interaction with Asn132. Based on the crystal structure, further modifications of CVT-313 are proposed to provide additional interactions with CDK2 in the active site, which may significantly increase the biochemical and cellular potency of CVT-313. PubMed: 32744246DOI: 10.1107/S2053230X20009243 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.75 Å) |
Structure validation
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