6ue6

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PWWP1 domain of NSD2 in complex with MR837

Structural highlights

6ue6 is a 8 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.4Å
Ligands:Q5D, UNX
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

NSD2_HUMAN Wolf-Hirschhorn syndrome. A chromosomal aberration involving WHSC1 is a cause of multiple myeloma tumors. Translocation t(4;14)(p16.3;q32.3) with IgH. WHSC1 is located in the Wolf-Hirschhorn syndrome (WHS) critical region. WHS results from by sub-telomeric deletions in the short arm of chromosome 4. WHSC1 is deleted in every case, however deletion of linked genes contributes to both the severity of the core characteristics and the presence of the additional syndromic problems.

Function

NSD2_HUMAN Histone methyltransferase with histone H3 'Lys-27' (H3K27me) methyltransferase activity. Isoform 2 may act as a transcription regulator that binds DNA and suppresses IL5 transcription through HDAC recruitment.[1] [2] [3]

Publication Abstract from PubMed

Increased activity of the lysine methyltransferase NSD2 driven by translocation and activating mutations is associated with multiple myeloma and acute lymphoblastic leukemia, but no NSD2-targeting chemical probe has been reported to date. Here, we present the first antagonists that block the protein-protein interaction between the N-terminal PWWP domain of NSD2 and H3K36me2. Using virtual screening and experimental validation, we identified the small-molecule antagonist 3f, which binds to the NSD2-PWWP1 domain with a Kd of 3.4 muM and abrogates histone H3K36me2 binding to the PWWP1 domain in cells. This study establishes an alternative approach to targeting NSD2 and provides a small-molecule antagonist that can be further optimized into a chemical probe to better understand the cellular function of this protein.

Discovery of Small-Molecule Antagonists of the PWWP Domain of NSD2.,Ferreira de Freitas R, Liu Y, Szewczyk MM, Mehta N, Li F, McLeod D, Zepeda-Velazquez C, Dilworth D, Hanley RP, Gibson E, Brown PJ, Al-Awar R, James LI, Arrowsmith CH, Barsyte-Lovejoy D, Min J, Vedadi M, Schapira M, Allali-Hassani A J Med Chem. 2021 Feb 11;64(3):1584-1592. doi: 10.1021/acs.jmedchem.0c01768. Epub , 2021 Feb 1. PMID:33522809[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ Garlisi CG, Uss AS, Xiao H, Tian F, Sheridan KE, Wang L, Motasim Billah M, Egan RW, Stranick KS, Umland SP. A unique mRNA initiated within a middle intron of WHSC1/MMSET encodes a DNA binding protein that suppresses human IL-5 transcription. Am J Respir Cell Mol Biol. 2001 Jan;24(1):90-98. PMID:11152655
  2. ↑ Hudlebusch HR, Theilgaard-Monch K, Lodahl M, Johnsen HE, Rasmussen T. Identification of ID-1 as a potential target gene of MMSET in multiple myeloma. Br J Haematol. 2005 Sep;130(5):700-8. PMID:16115125 doi:http://dx.doi.org/BJH5664
  3. ↑ Kim JY, Kee HJ, Choe NW, Kim SM, Eom GH, Baek HJ, Kook H, Kook H, Seo SB. Multiple-myeloma-related WHSC1/MMSET isoform RE-IIBP is a histone methyltransferase with transcriptional repression activity. Mol Cell Biol. 2008 Mar;28(6):2023-34. doi: 10.1128/MCB.02130-07. Epub 2008 Jan, 2. PMID:18172012 doi:http://dx.doi.org/10.1128/MCB.02130-07
  4. ↑ Ferreira de Freitas R, Liu Y, Szewczyk MM, Mehta N, Li F, McLeod D, Zepeda-Velazquez C, Dilworth D, Hanley RP, Gibson E, Brown PJ, Al-Awar R, James LI, Arrowsmith CH, Barsyte-Lovejoy D, Min J, Vedadi M, Schapira M, Allali-Hassani A. Discovery of Small-Molecule Antagonists of the PWWP Domain of NSD2. J Med Chem. 2021 Feb 11;64(3):1584-1592. doi: 10.1021/acs.jmedchem.0c01768. Epub , 2021 Feb 1. PMID:33522809 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c01768

Contents


PDB ID 6ue6

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OCA

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