6V0P
PRMT5 complex bound to covalent PBM inhibitor BRD6711
Summary for 6V0P
| Entry DOI | 10.2210/pdb6v0p/pdb |
| Descriptor | Protein arginine N-methyltransferase 5, Methylosome protein 50, 2-(5-chloro-6-oxopyridazin-1(6H)-yl)-N-(4-methyl-3-sulfamoylphenyl)acetamide, ... (7 entities in total) |
| Functional Keywords | methyltransferase, splicing, sdma, epigenetic, splicing-transferase complex, splicing/transferase |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 110483.09 |
| Authors | McMillan, B.J.,McKinney, D.C. (deposition date: 2019-11-19, release date: 2020-11-25, Last modification date: 2024-10-23) |
| Primary citation | McKinney, D.C.,McMillan, B.J.,Ranaghan, M.J.,Moroco, J.A.,Brousseau, M.,Mullin-Bernstein, Z.,O'Keefe, M.,McCarren, P.,Mesleh, M.F.,Mulvaney, K.M.,Robinson, F.,Singh, R.,Bajrami, B.,Wagner, F.F.,Hilgraf, R.,Drysdale, M.J.,Campbell, A.J.,Skepner, A.,Timm, D.E.,Porter, D.,Kaushik, V.K.,Sellers, W.R.,Ianari, A. Discovery of a First-in-Class Inhibitor of the PRMT5-Substrate Adaptor Interaction. J.Med.Chem., 64:11148-11168, 2021 Cited by PubMed Abstract: PRMT5 and its substrate adaptor proteins (SAPs), pICln and Riok1, are synthetic lethal dependencies in MTAP-deleted cancer cells. SAPs share a conserved PRMT5 binding motif (PBM) which mediates binding to a surface of PRMT5 distal to the catalytic site. This interaction is required for methylation of several PRMT5 substrates, including histone and spliceosome complexes. We screened for small molecule inhibitors of the PRMT5-PBM interaction and validated a compound series which binds to the PRMT5-PBM interface and directly inhibits binding of SAPs. Mode of action studies revealed the formation of a covalent bond between a halogenated pyridazinone group and cysteine 278 of PRMT5. Optimization of the starting hit produced a lead compound, BRD0639, which engages the target in cells, disrupts PRMT5-RIOK1 complexes, and reduces substrate methylation. BRD0639 is a first-in-class PBM-competitive inhibitor that can support studies of PBM-dependent PRMT5 activities and the development of novel PRMT5 inhibitors that selectively target these functions. PubMed: 34342224DOI: 10.1021/acs.jmedchem.1c00507 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.88 Å) |
Structure validation
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