7ORE
Crystal structure of JNK3 in complex with light-activated covalent inhibitor MR-II-249 with both non-covalent and covalent binding modes (compound 4)
Summary for 7ORE
| Entry DOI | 10.2210/pdb7ore/pdb |
| Descriptor | Mitogen-activated protein kinase 10, 4-(dimethylamino)-N-[(5Z)-9-[[4-[5-(4-fluorophenyl)-3-methyl-2-methylsulfanyl-imidazol-4-yl]pyridin-2-yl]amino]-11,12-dihydrobenzo[c][1,2]benzodiazocin-2-yl]butanamide, 1,2-ETHANEDIOL, ... (4 entities in total) |
| Functional Keywords | kinase, mapk, mapk10, light activation, covalent inhibitor, structural genomics, structural genomics consortium, sgc, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 44002.95 |
| Authors | Chaikuad, A.,Reynders, M.,Trauner, D.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2021-06-05, release date: 2021-07-21, Last modification date: 2024-01-31) |
| Primary citation | Reynders, M.,Chaikuad, A.,Berger, B.T.,Bauer, K.,Koch, P.,Laufer, S.,Knapp, S.,Trauner, D. Controlling the Covalent Reactivity of a Kinase Inhibitor with Light. Angew.Chem.Int.Ed.Engl., 60:20178-20183, 2021 Cited by PubMed Abstract: Covalent kinase inhibitors account for some of the most successful drugs that have recently entered the clinic and many others are in preclinical development. A common strategy is to target cysteines in the vicinity of the ATP binding site using an acrylamide electrophile. To increase the tissue selectivity of kinase inhibitors, it could be advantageous to control the reactivity of these electrophiles with light. Here, we introduce covalent inhibitors of the kinase JNK3 that function as photoswitchable affinity labels (PALs). Our lead compounds contain a diazocine photoswitch, are poor non-covalent inhibitors in the dark, and become effective covalent inhibitors after irradiation with visible light. Our proposed mode of action is supported by X-ray structures that explain why these compounds are unreactive in the dark and undergo proximity-based covalent attachment following exposure to light. PubMed: 34081840DOI: 10.1002/anie.202103767 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.18 Å) |
Structure validation
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