6KQQ
NSD1 SET domain in complex with BT3 and SAM
Summary for 6KQQ
| Entry DOI | 10.2210/pdb6kqq/pdb |
| Descriptor | Histone-lysine N-methyltransferase, H3 lysine-36 and H4 lysine-20 specific, S-ADENOSYLMETHIONINE, 2-azanyl-6-sulfanyl-1,3-benzothiazol-4-ol, ... (8 entities in total) |
| Functional Keywords | histone-methyltransferase, sam, inhibitor complex, transferase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 52880.55 |
| Authors | Cho, H.J.,Cierpicki, T. (deposition date: 2019-08-18, release date: 2020-09-02, Last modification date: 2024-10-09) |
| Primary citation | Huang, H.,Howard, C.A.,Zari, S.,Cho, H.J.,Shukla, S.,Li, H.,Ndoj, J.,Gonzalez-Alonso, P.,Nikolaidis, C.,Abbott, J.,Rogawski, D.S.,Potopnyk, M.A.,Kempinska, K.,Miao, H.,Purohit, T.,Henderson, A.,Mapp, A.,Sulis, M.L.,Ferrando, A.,Grembecka, J.,Cierpicki, T. Covalent inhibition of NSD1 histone methyltransferase. Nat.Chem.Biol., 16:1403-1410, 2020 Cited by PubMed Abstract: The nuclear receptor-binding SET domain (NSD) family of histone methyltransferases is associated with various malignancies, including aggressive acute leukemia with NUP98-NSD1 translocation. While NSD proteins represent attractive drug targets, their catalytic SET domains exist in autoinhibited conformation, presenting notable challenges for inhibitor development. Here, we employed a fragment-based screening strategy followed by chemical optimization, which resulted in the development of the first-in-class irreversible small-molecule inhibitors of the nuclear receptor-binding SET domain protein 1 (NSD1) SET domain. The crystal structure of NSD1 in complex with covalently bound ligand reveals a conformational change in the autoinhibitory loop of the SET domain and formation of a channel-like pocket suitable for targeting with small molecules. Our covalent lead-compound BT5-demonstrates on-target activity in NUP98-NSD1 leukemia cells, including inhibition of histone H3 lysine 36 dimethylation and downregulation of target genes, and impaired colony formation in an NUP98-NSD1 patient sample. This study will facilitate the development of the next generation of potent and selective inhibitors of the NSD histone methyltransferases. PubMed: 32868895DOI: 10.1038/s41589-020-0626-6 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.8 Å) |
Structure validation
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