3SR4
Crystal Structure of Human DOT1L in Complex with a Selective Inhibitor
Summary for 3SR4
| Entry DOI | 10.2210/pdb3sr4/pdb |
| Related | 1NW3 3QOW 3QOX |
| Descriptor | Histone-lysine N-methyltransferase, H3 lysine-79 specific, (2S)-2-azanyl-4-[[(2S,3S,4R,5R)-5-[6-(methylamino)purin-9-yl]-3,4-bis(oxidanyl)oxolan-2-yl]methylsulfanyl]butanoic acid, GLYCEROL, ... (6 entities in total) |
| Functional Keywords | hdot1, histone lysine methyltransferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Nucleus (Probable): Q8TEK3 |
| Total number of polymer chains | 1 |
| Total formula weight | 41396.86 |
| Authors | Diao, J.,Chen, P.,Yao, Y.,Prasad, B.V.V.,Song, Y. (deposition date: 2011-07-06, release date: 2011-10-05, Last modification date: 2023-09-13) |
| Primary citation | Yao, Y.,Chen, P.,Diao, J.,Cheng, G.,Deng, L.,Anglin, J.L.,Prasad, B.V.,Song, Y. Selective Inhibitors of Histone Methyltransferase DOT1L: Design, Synthesis, and Crystallographic Studies. J.Am.Chem.Soc., 133:16746-16749, 2011 Cited by PubMed Abstract: Histone H3-lysine79 (H3K79) methyltransferase DOT1L plays critical roles in normal cell differentiation as well as initiation of acute leukemia. We used structure- and mechanism-based design to discover several potent inhibitors of DOT1L with IC(50) values as low as 38 nM. These inhibitors exhibit only weak or no activities against four other representative histone lysine and arginine methyltransferases, G9a, SUV39H1, PRMT1 and CARM1. The X-ray crystal structure of a DOT1L-inhibitor complex reveals that the N6-methyl group of the inhibitor, located favorably in a predominantly hydrophobic cavity of DOT1L, provides the observed high selectivity. Structural analysis shows that it will disrupt at least one H-bond and/or have steric repulsion for other histone methyltransferases. These compounds represent novel chemical probes for biological function studies of DOT1L in health and disease. PubMed: 21936531DOI: 10.1021/ja206312b PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
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