6P3D
The co-crystal structure of BRAF(V600E) with ponatinib
Summary for 6P3D
| Entry DOI | 10.2210/pdb6p3d/pdb |
| Descriptor | Serine/threonine-protein kinase B-raf, 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzam ide, SULFATE ION, ... (6 entities in total) |
| Functional Keywords | kinase, inhibitor, cancer, melanoma, transferase-transferase inhibitor complex, oncoprotein, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 35195.90 |
| Authors | Agianian, B.,Gavathiotis, E. (deposition date: 2019-05-23, release date: 2020-09-23, Last modification date: 2024-03-13) |
| Primary citation | Cotto-Rios, X.M.,Agianian, B.,Gitego, N.,Zacharioudakis, E.,Giricz, O.,Wu, Y.,Zou, Y.,Verma, A.,Poulikakos, P.I.,Gavathiotis, E. Inhibitors of BRAF dimers using an allosteric site. Nat Commun, 11:4370-4370, 2020 Cited by PubMed Abstract: BRAF kinase, a critical effector of the ERK signaling pathway, is hyperactivated in many cancers. Oncogenic BRAF signals as an active monomer in the absence of active RAS, however, in many tumors BRAF dimers mediate ERK signaling. FDA-approved RAF inhibitors poorly inhibit BRAF dimers, which leads to tumor resistance. We found that Ponatinib, an FDA-approved drug, is an effective inhibitor of BRAF monomers and dimers. Ponatinib binds the BRAF dimer and stabilizes a distinct αC-helix conformation through interaction with a previously unrevealed allosteric site. Using these structural insights, we developed PHI1, a BRAF inhibitor that fully uncovers the allosteric site. PHI1 exhibits discrete cellular selectivity for BRAF dimers, with enhanced inhibition of the second protomer when the first protomer is occupied, comprising a novel class of dimer selective inhibitors. This work shows that Ponatinib and BRAF dimer selective inhibitors will be useful in treating BRAF-dependent tumors. PubMed: 32873792DOI: 10.1038/s41467-020-18123-2 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.11 Å) |
Structure validation
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