Summary for 6CHH
| Entry DOI | 10.2210/pdb6chh/pdb |
| Descriptor | Nicotinamide N-methyltransferase, (2~{S})-5-[2-(3-aminocarbonylphenyl)ethyl-[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl]amino]-2-azanyl-pentanoic acid, 1,2-ETHANEDIOL, ... (4 entities in total) |
| Functional Keywords | protein-small molecule bisubstrate inhibitor complex, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 128102.51 |
| Authors | Babault, N.,Liu, J.,Jin, J. (deposition date: 2018-02-22, release date: 2018-06-13, Last modification date: 2023-10-04) |
| Primary citation | Babault, N.,Allali-Hassani, A.,Li, F.,Fan, J.,Yue, A.,Ju, K.,Liu, F.,Vedadi, M.,Liu, J.,Jin, J. Discovery of Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT). J. Med. Chem., 61:1541-1551, 2018 Cited by PubMed Abstract: Nicotinamide N-methyltransferase (NNMT) catalyzes the N-methylation of pyridine-containing compounds using the cofactor S-5'-adenosyl-l-methionine (SAM) as the methyl group donor. Through the regulation of the levels of its substrates, cofactor, and products, NNMT plays an important role in physiology and pathophysiology. Overexpression of NNMT has been implicated in various human diseases. Potent and selective small-molecule NNMT inhibitors are valuable chemical tools for testing biological and therapeutic hypotheses. However, very few NNMT inhibitors have been reported. Here, we describe the discovery of a bisubstrate NNMT inhibitor MS2734 (6) and characterization of this inhibitor in biochemical, biophysical, kinetic, and structural studies. Importantly, we obtained the first crystal structure of human NNMT in complex with a small-molecule inhibitor. The structure of the NNMT-6 complex has unambiguously demonstrated that 6 occupied both substrate and cofactor binding sites. The findings paved the way for developing more potent and selective NNMT inhibitors in the future. PubMed: 29320176DOI: 10.1021/acs.jmedchem.7b01422 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3 Å) |
Structure validation
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