7vln

From Proteopedia

(Difference between revisions)

Current revision

NSD2-PWWP1 domain bound with an imidazol-5-yl benzonitrile compound

Structural highlights

7vln is a 3 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 3.09Å
Ligands:
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

Overexpression, point mutations, or translocations of protein lysine methyltransferase NSD2 occur in many types of cancer cells. Therefore, it was recognized as onco-protein and considered as a promising anticancer drug target. NSD2 consists of multiple domains including a SET catalytic domain and two PWWP domains binding to methylated histone proteins. Here, we reported our efforts to develop a series of NSD2-PWWP1 inhibitors, and further structure-based optimization resulted in a potent inhibitor 38, which has high selectivity toward the NSD2-PWWP1 domain. The detailed biological evaluation revealed that compound 38 can bind to NSD2-PWWP1 and then affect the expression of genes regulated by NSD2. The current discovery will provide a useful chemical probe to the future research in understanding the specific regulation mode of NSD2 by PWWP1 recognition and pave the way to develop potential drugs targeting NSD2 protein.

Structure-Based Discovery of a Series of NSD2-PWWP1 Inhibitors.,Li N, Yang H, Liu K, Zhou L, Huang Y, Cao D, Li Y, Sun Y, Yu A, Du Z, Yu F, Zhang Y, Wang B, Geng M, Li J, Xiong B, Xu S, Huang X, Liu T J Med Chem. 2022 Jun 15. doi: 10.1021/acs.jmedchem.2c00709. PMID:35704853^[4]

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

References

↑ 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
↑ 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
↑ 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
↑ Li N, Yang H, Liu K, Zhou L, Huang Y, Cao D, Li Y, Sun Y, Yu A, Du Z, Yu F, Zhang Y, Wang B, Geng M, Li J, Xiong B, Xu S, Huang X, Liu T. Structure-Based Discovery of a Series of NSD2-PWWP1 Inhibitors. J Med Chem. 2022 Jun 15. doi: 10.1021/acs.jmedchem.2c00709. PMID:35704853 doi:http://dx.doi.org/10.1021/acs.jmedchem.2c00709

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7vln"

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[7vln]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7VLN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7VLN FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7QC:4-[5-[4-(aminomethyl)-2,6-dimethoxy-phenyl]-3-methyl-imidazol-4-yl]benzenecarbonitrile'>7QC</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.09&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7QC:4-[5-[4-(aminomethyl)-2,6-dimethoxy-phenyl]-3-methyl-imidazol-4-yl]benzenecarbonitrile'>7QC</scene></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7vln FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7vln OCA], [https://pdbe.org/7vln PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7vln RCSB], [https://www.ebi.ac.uk/pdbsum/7vln PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7vln ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[https://www.uniprot.org/uniprot/NSD2_HUMAN 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.
+[https://www.uniprot.org/uniprot/NSD2_HUMAN 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 ==
-[[https://www.uniprot.org/uniprot/NSD2_HUMAN 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.<ref>PMID:11152655</ref> <ref>PMID:16115125</ref> <ref>PMID:18172012</ref>
+[https://www.uniprot.org/uniprot/NSD2_HUMAN 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.<ref>PMID:11152655</ref> <ref>PMID:16115125</ref> <ref>PMID:18172012</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==

7vln

From Proteopedia

Current revision

NSD2-PWWP1 domain bound with an imidazol-5-yl benzonitrile compound

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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