7E8D
NSD2 E1099K mutant bound to nucleosome
Summary for 7E8D
| Entry DOI | 10.2210/pdb7e8d/pdb |
| EMDB information | 31015 |
| Descriptor | Histone H3.1, Histone H4, Histone H2A type 1, ... (9 entities in total) |
| Functional Keywords | chromatin, epigenetics, histone methyltransferase, muitiple myeloma, gene regulation |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 11 |
| Total formula weight | 252528.67 |
| Authors | Sengoku, T.,Sato, K.,Nishizawa, T.,Nureki, O.,Ogata, K. (deposition date: 2021-03-01, release date: 2021-11-10, Last modification date: 2024-06-05) |
| Primary citation | Sato, K.,Kumar, A.,Hamada, K.,Okada, C.,Oguni, A.,Machiyama, A.,Sakuraba, S.,Nishizawa, T.,Nureki, O.,Kono, H.,Ogata, K.,Sengoku, T. Structural basis of the regulation of the normal and oncogenic methylation of nucleosomal histone H3 Lys36 by NSD2. Nat Commun, 12:6605-6605, 2021 Cited by PubMed Abstract: Dimethylated histone H3 Lys36 (H3K36me2) regulates gene expression, and aberrant H3K36me2 upregulation, resulting from either the overexpression or point mutation of the dimethyltransferase NSD2, is found in various cancers. Here we report the cryo-electron microscopy structure of NSD2 bound to the nucleosome. Nucleosomal DNA is partially unwrapped, facilitating NSD2 access to H3K36. NSD2 interacts with DNA and H2A along with H3. The NSD2 autoinhibitory loop changes its conformation upon nucleosome binding to accommodate H3 in its substrate-binding cleft. Kinetic analysis revealed that two oncogenic mutations, E1099K and T1150A, increase NSD2 catalytic turnover. Molecular dynamics simulations suggested that in both mutants, the autoinhibitory loop adopts an open state that can accommodate H3 more often than the wild-type. We propose that E1099K and T1150A destabilize the interactions that keep the autoinhibitory loop closed, thereby enhancing catalytic turnover. Our analyses guide the development of specific inhibitors of NSD2. PubMed: 34782608DOI: 10.1038/s41467-021-26913-5 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.8 Å) |
Structure validation
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