9MGN
Crystal structure of PRMT5:MEP50 in complex with MTA and compound 41
This is a non-PDB format compatible entry.
Summary for 9MGN
| Entry DOI | 10.2210/pdb9mgn/pdb |
| Descriptor | Protein arginine N-methyltransferase 5, Methylosome protein 50, 2-(cyclobutylamino)-N-[(2S)-2-hydroxy-3-{6-[(1H-pyrazol-4-yl)methoxy]-3,4-dihydroisoquinolin-2(1H)-yl}propyl]pyridine-4-carboxamide, ... (7 entities in total) |
| Functional Keywords | methyltransferase, inhibitor, mtap-null, transferase, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 112616.17 |
| Authors | |
| Primary citation | Cottrell, K.M.,Whittington, D.A.,Briggs, K.J.,Jahic, H.,Ali, J.A.,Amor, A.J.,Gotur, D.,Tonini, M.R.,Zhang, W.,Huang, A.,Maxwell, J.P. MTA-Cooperative PRMT5 Inhibitors: Mechanism Switching Through Structure-Based Design. J.Med.Chem., 68:4217-4236, 2025 Cited by PubMed Abstract: Deletion of the gene leads to accumulation of the substrate of the MTAP protein, methylthioadenosine (MTA). MTA binds PRMT5 competitively with S-adenosyl-l-methionine (SAM), and selective inhibition of the PRMT5•MTA complex relative to the PRMT5•SAM complex can lead to selective killing of cancer cells with deletion. Herein, we describe the discovery of novel compounds using structure-based drug design to switch the mechanism of binding of known, SAM-cooperative PRMT5 inhibitors to an MTA-cooperative binding mechanism by occupying the portion of the SAM binding pocket in PRMT5 that is unoccupied when MTA is bound and hydrogen bonding to Arg368, thereby allowing them to selectively target -deleted cancer cells. PubMed: 39919252DOI: 10.1021/acs.jmedchem.4c01998 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.82 Å) |
Structure validation
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