6XCG

Histone-lysine N-methyltransferase NSD2-PWWP1 with compound UNC6934

Summary for 6XCG

• Entry DOI: 10.2210/pdb6xcg/pdb
• Descriptor: Histone-lysine N-methyltransferase NSD2, N-cyclopropyl-3-oxo-N-({4-[(pyrimidin-4-yl)carbamoyl]phenyl}methyl)-3,4-dihydro-2H-1,4-benzoxazine-7-carboxamide, UNKNOWN ATOM OR ION, ... (4 entities in total)
• Functional Keywords: nsd2-pwwp, structural genomics, structural genomics consortium, sgc, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 3
• Total formula weight: 49770.30

Authors

Zhou, M.Q.,Dong, A.,Ingerman, L.A.,Hanley, R.P.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.M.,Min, J.,Structural Genomics Consortium (SGC) (deposition date: 2020-06-08, release date: 2020-07-22, Last modification date: 2023-10-18)

Primary citation

Dilworth, D.,Hanley, R.P.,Ferreira de Freitas, R.,Allali-Hassani, A.,Zhou, M.,Mehta, N.,Marunde, M.R.,Ackloo, S.,Carvalho Machado, R.A.,Khalili Yazdi, A.,Owens, D.D.G.,Vu, V.,Nie, D.Y.,Alqazzaz, M.,Marcon, E.,Li, F.,Chau, I.,Bolotokova, A.,Qin, S.,Lei, M.,Liu, Y.,Szewczyk, M.M.,Dong, A.,Kazemzadeh, S.,Abramyan, T.,Popova, I.K.,Hall, N.W.,Meiners, M.J.,Cheek, M.A.,Gibson, E.,Kireev, D.,Greenblatt, J.F.,Keogh, M.C.,Min, J.,Brown, P.J.,Vedadi, M.,Arrowsmith, C.H.,Barsyte-Lovejoy, D.,James, L.I.,Schapira, M.
A chemical probe targeting the PWWP domain alters NSD2 nucleolar localization.
Nat.Chem.Biol., 18:56-63, 2022

PubMed Abstract: Nuclear receptor-binding SET domain-containing 2 (NSD2) is the primary enzyme responsible for the dimethylation of lysine 36 of histone 3 (H3K36), a mark associated with active gene transcription and intergenic DNA methylation. In addition to a methyltransferase domain, NSD2 harbors two proline-tryptophan-tryptophan-proline (PWWP) domains and five plant homeodomains (PHDs) believed to serve as chromatin reading modules. Here, we report a chemical probe targeting the N-terminal PWWP (PWWP1) domain of NSD2. UNC6934 occupies the canonical H3K36me2-binding pocket of PWWP1, antagonizes PWWP1 interaction with nucleosomal H3K36me2 and selectively engages endogenous NSD2 in cells. UNC6934 induces accumulation of endogenous NSD2 in the nucleolus, phenocopying the localization defects of NSD2 protein isoforms lacking PWWP1 that result from translocations prevalent in multiple myeloma (MM). Mutations of other NSD2 chromatin reader domains also increase NSD2 nucleolar localization and enhance the effect of UNC6934. This chemical probe and the accompanying negative control UNC7145 will be useful tools in defining NSD2 biology.

PubMed: 34782742
DOI: 10.1038/s41589-021-00898-0

Experimental method

X-RAY DIFFRACTION (1.64 Å)