9Y61
Cryo-EM structure of ternary complex NSD2-PWWP1:CRBN:DDB1 in complex with NSD2-LDD, an LDD degrader
This is a non-PDB format compatible entry.
Summary for 9Y61
| Entry DOI | 10.2210/pdb9y61/pdb |
| EMDB information | 72526 |
| Descriptor | Histone-lysine N-methyltransferase NSD2, Protein cereblon, 1-(5-{9-[(4-{2-[(2S,3R)-2-(3,5-dichloro-4-fluorophenyl)-5-oxomorpholin-3-yl]ethyl}piperazin-1-yl)methyl]-3-azaspiro[5.5]undecane-3-carbonyl}-2-methylphenyl)-1,3-diazinane-2,4-dione, ... (4 entities in total) |
| Functional Keywords | cereblon, degrader, ddb1, nsd2, pwwp1, ldd, ligase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 74237.85 |
| Authors | |
| Primary citation | Hu, B.,Edwards, J.,Modi, H.,Gamez, J.,Echeagaray, O.E.,Hess, K.,Ren, Y.,Anderson, D.,Larrayoz, M.,Zhu, J.,Johnson, S.A.,Deb, G.,Jankeel, D.,Janardhanan, P.,Leisten, J.,Peng, S.,Christoforou, A.,Stong, N.,Fontanillo, C.,Bjorklund, C.C.,Hagner, P.R.,Gandhi, A.K.,Martinez-Climent, J.A.,Narla, R.K.,Lopez-Girona, A.,Rolfe, M.,Bence, N.,Mortensen, D.S.,Groocock, L. NSD2 Degradation Remediates the Oncogenic Cistrome in t(4;14) Multiple Myeloma. Blood, 2026 Cited by PubMed Abstract: The t(4;14) chromosomal translocation drives overexpression of the histone methyltransferase NSD2 and defines a high-risk segment of multiple myeloma (MM) patients. Herein, we report the discovery of NSD2-LDD, a cereblon-recruiting and PWWP1-mediated ligand directed degrader (LDD) that selectively and potently eliminates full length and PWWP1 domain containing NSD2 protein isoforms. NSD2-LDD treatment induces global loss of H3K36me2 leading to promoter-proximal spreading of H3K27me3 and re-wiring of cis-regulatory interactions that reverse t(4;14) transcriptional programs. These effects suppress MM disease-associated phenotypes including stromal adhesion, three-dimensional colony growth and paracrine signaling. By integrating patient single cell profiles with model 3D epigenomic and spatial transcriptomics, we delineate t(4;14) disease state together with the tumor-intrinsic reprogramming and resultant remodeling of the bone marrow microenvironment upon NSD2 degradation. In cell line derived xenografts and genetically engineered mouse models of t(4;14), NSD2-LDD extends median survival accompanied by tumoral H3K36me2 loss and niche re-modelling. Although the NSD2-LDD response is restricted to PWWP1-containining models, collectively this work validates NSD2 as a tractable dependency and supports clinical development of NSD2 degradation as a novel, targeted therapeutic strategy in high-risk MM. PubMed: 42371798DOI: 10.1182/blood.2025031998 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.1 Å) |
Structure validation
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