9VPQ
Crystal structure of METTL9 in complex with compound 15k
This is a non-PDB format compatible entry.
Summary for 9VPQ
| Entry DOI | 10.2210/pdb9vpq/pdb |
| Descriptor | Protein-L-histidine N-pros-methyltransferase, Zinc transporter ZIP5, ~{N}-[2-fluoranyl-5-[8-fluoranyl-4-[(3-hydroxyphenyl)amino]quinazolin-6-yl]pyridin-3-yl]benzenesulfonamide, ... (4 entities in total) |
| Functional Keywords | protein-l-histidine n-pros-methyltransferase, inhibitor, complex, transferase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 66152.87 |
| Authors | |
| Primary citation | Yao, R.,Zhang, G.,Huang, Y.,Fan, D.,Zhang, H.,Qiao, J.,Chen, C.,Shao, Z.,Li, L.,Yang, S. Discovery of a Potent and Selective Cell-Active Inhibitor of Histidine-N1 Methyltransferase METTL9. Angew.Chem.Int.Ed.Engl., 65:e3642560-e3642560, 2026 Cited by PubMed Abstract: Protein histidine N1-methylation (1-methylhistidine, 1-MH) is a prevalent yet underexplored post-translational modification in mammals. The methyltransferase METTL9 acts as an important enzyme catalyzing 1-MH of histidine in diverse protein substrates, with mounting evidence suggesting its involvement in tumor progression. Despite its potential significance, no inhibitors targeting METTL9 have been previously identified. Here, we introduce compound METTL9i as a first-in-class, highly potent, and selective METTL9 inhibitor. METTL9i inhibits METTL9 with a half-maximum inhibitory concentration (IC) of 0.067 ± 0.009 µM and exhibits selectivity over other methyltransferases. Structural analysis via crystallography reveals that METTL9i binds within the S-adenosylmethionine (SAM) binding pocket. In cells, METTL9i engages METTL9 and leads to a reduction in global 1-MH levels. These results support METTL9i as a useful tool compound for investigating METTL9 biology and the functions of histidine 1-MH, while also serving as a promising lead compound for drug discovery targeting METTL9. PubMed: 41870122DOI: 10.1002/anie.3642560 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.28 Å) |
Structure validation
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