9ATV
X-ray co-crystal structure of NCGC00685960 / NCATS-SM9335 in NNMT
This is a non-PDB format compatible entry.
Summary for 9ATV
| Entry DOI | 10.2210/pdb9atv/pdb |
| Descriptor | Nicotinamide N-methyltransferase, (8M)-8-{3-[(3S)-1-(2-cyclohexylethyl)piperidin-3-yl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl}quinolin-2(1H)-one (3 entities in total) |
| Functional Keywords | nnmt, inhibitor, tumor, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 3 |
| Total formula weight | 95662.70 |
| Authors | Olland, A.,White, A.,Suto, R. (deposition date: 2024-02-27, release date: 2025-03-05, Last modification date: 2025-10-08) |
| Primary citation | Heide, J.,Bilecz, A.J.,Patnaik, S.,Allega, M.F.,Donle, L.,Yang, K.,Teich, E.,Li, Y.,Lin, Q.,Kong, K.,Liu, L.,Yang, T.G.,Cheng, K.C.,Shrimp, J.H.,Hanson, Q.M.,Shen, M.,Sun, H.,Shah, H.,Schweizer, L.,Zawieracz, K.,Olland, A.,White, A.,Suto, R.K.,Alhunayan, R.,Tasdemir, M.,Longman, N.,Liang, H.,Mann, M.,Stott, G.M.,Hall, M.D.,Schworer, S.,Weichselbaum, R.R.,Piffko, A.,Lengyel, E. NNMT inhibition in cancer-associated fibroblasts restores antitumour immunity. Nature, 645:1051-1059, 2025 Cited by PubMed Abstract: Cancer-associated fibroblasts (CAFs) have a pivotal cancer-supportive role, yet CAF-targeted therapies are lacking. Here, using spatial transcriptomics and single-cell RNA sequencing, we investigate the role of nicotinamide N-methyltransferase (NNMT) in high-grade serous ovarian cancer. Mechanistically, NNMT-induced H3K27me3 hypomethylation drives complement secretion from CAFs, attracting immunosuppressive myeloid-derived suppressor cells (MDSCs) to the tumour. Nnmt knockout in immunocompetent mice impairs tumour growth in syngeneic ovarian, breast and colon tumour models through enhanced CD8 T cell activation. Using high-throughput screening, we develop a potent and specific NNMT inhibitor that reduces the tumour burden and metastasis in multiple mouse cancer models and restores immune checkpoint blockade efficacy by decreasing CAF-mediated recruitment of MDSCs and reinvigorating CD8 T cell activation. Our findings establish NNMT as a central CAF regulator and a promising therapeutic target to mitigate immunosuppression in the tumour microenvironment. PubMed: 40702186DOI: 10.1038/s41586-025-09303-5 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.413 Å) |
Structure validation
Download full validation report
