5lsu

From Proteopedia

(Difference between revisions)

Revision as of 21:43, 5 October 2016

Structure of the Epigenetic Oncogene MMSET and inhibition by N-Alkyl Sinefungin Derivatives

Structural highlights

5lsu is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Activity:	Histone-lysine N-methyltransferase, with EC number 2.1.1.43
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

The members of the NSD subfamily of lysine methyl transferases are compelling oncology targets due to the recent characterization of gain-of-function mutations and translocations in several hematological cancers. To date, these proteins have proven intractable to small molecule inhibition. Here, we present initial efforts to identify inhibitors of MMSET (aka NSD2 or WHSC1) using solution phase and crystal structural methods. On the basis of 2D NMR experiments comparing NSD1 and MMSET structural mobility, we designed an MMSET construct with five point mutations in the N-terminal helix of its SET domain for crystallization experiments and elucidated the structure of the mutant MMSET SET domain at 2.1 A resolution. Both NSD1 and MMSET crystal systems proved resistant to soaking or cocrystallography with inhibitors. However, use of the close homologue SETD2 as a structural surrogate supported the design and characterization of N-alkyl sinefungin derivatives, which showed low micromolar inhibition against both SETD2 and MMSET.

Structure of the Epigenetic Oncogene MMSET and Inhibition by N-Alkyl Sinefungin Derivatives.,Tisi D, Chiarparin E, Tamanini E, Pathuri P, Coyle JE, Hold A, Holding FP, Amin N, Martin AC, Rich SJ, Berdini V, Yon J, Acklam P, Burke R, Drouin L, Harmer JE, Jeganathan F, van Montfort RL, Newbatt Y, Tortorici M, Westlake M, Wood A, Hoelder S, Heightman TD ACS Chem Biol. 2016 Sep 27. PMID:27571355^[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
↑ Tisi D, Chiarparin E, Tamanini E, Pathuri P, Coyle JE, Hold A, Holding FP, Amin N, Martin AC, Rich SJ, Berdini V, Yon J, Acklam P, Burke R, Drouin L, Harmer JE, Jeganathan F, van Montfort RL, Newbatt Y, Tortorici M, Westlake M, Wood A, Hoelder S, Heightman TD. Structure of the Epigenetic Oncogene MMSET and Inhibition by N-Alkyl Sinefungin Derivatives. ACS Chem Biol. 2016 Sep 27. PMID:27571355 doi:http://dx.doi.org/10.1021/acschembio.6b00308

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/5lsu"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 5lsu is ON HOLD  until Paper Publication
+==Structure of the Epigenetic Oncogene MMSET and inhibition by N-Alkyl Sinefungin Derivatives==
+<StructureSection load='5lsu' size='340' side='right' caption='[[5lsu]], [[Resolution|resolution]] 2.14&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5lsu]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LSU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LSU FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone-lysine_N-methyltransferase Histone-lysine N-methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.43 2.1.1.43] </span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5lsu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lsu OCA], [http://pdbe.org/5lsu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5lsu RCSB], [http://www.ebi.ac.uk/pdbsum/5lsu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5lsu ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[[http://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 ==
+[[http://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 ==
+The members of the NSD subfamily of lysine methyl transferases are compelling oncology targets due to the recent characterization of gain-of-function mutations and translocations in several hematological cancers. To date, these proteins have proven intractable to small molecule inhibition. Here, we present initial efforts to identify inhibitors of MMSET (aka NSD2 or WHSC1) using solution phase and crystal structural methods. On the basis of 2D NMR experiments comparing NSD1 and MMSET structural mobility, we designed an MMSET construct with five point mutations in the N-terminal helix of its SET domain for crystallization experiments and elucidated the structure of the mutant MMSET SET domain at 2.1 A resolution. Both NSD1 and MMSET crystal systems proved resistant to soaking or cocrystallography with inhibitors. However, use of the close homologue SETD2 as a structural surrogate supported the design and characterization of N-alkyl sinefungin derivatives, which showed low micromolar inhibition against both SETD2 and MMSET.
-Authors: Tisi, D., Pathuri, P., Heightman, T.
+Structure of the Epigenetic Oncogene MMSET and Inhibition by N-Alkyl Sinefungin Derivatives.,Tisi D, Chiarparin E, Tamanini E, Pathuri P, Coyle JE, Hold A, Holding FP, Amin N, Martin AC, Rich SJ, Berdini V, Yon J, Acklam P, Burke R, Drouin L, Harmer JE, Jeganathan F, van Montfort RL, Newbatt Y, Tortorici M, Westlake M, Wood A, Hoelder S, Heightman TD ACS Chem Biol. 2016 Sep 27. PMID:27571355<ref>PMID:27571355</ref>
-Description: Structure of the Epigenetic Oncogene MMSET and inhibition by N-Alkyl Sinefungin Derivatives
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 5lsu" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Histone-lysine N-methyltransferase]]
 [[Category: Heightman, T]]
-[[Category: Tisi, D]]
 [[Category: Pathuri, P]]
+[[Category: Tisi, D]]
+[[Category: Lysine methyltransferase mmset set domain]]
+[[Category: Transferase]]

5lsu

From Proteopedia

Revision as of 21:43, 5 October 2016

Structure of the Epigenetic Oncogene MMSET and inhibition by N-Alkyl Sinefungin Derivatives

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

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