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5hq8

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Revision as of 08:27, 27 May 2020

Co-crystal Structure of human SMYD3 with a MEKK2 peptide at 2.13A

Structural highlights

5hq8 is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , ,
NonStd Res:
Gene:	SMYD3, ZMYND1, ZNFN3A1 (HUMAN)
Activity:	Histone-lysine N-methyltransferase, with EC number 2.1.1.43
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[SMYD3_HUMAN] Histone methyltransferase. Specifically methylates 'Lys-4' and 'Lys-5' of histone H3, inducing di- and tri-methylation, but not monomethylation. Plays an important role in transcriptional activation as a member of an RNA polymerase complex. Binds DNA containing 5'-CCCTCC-3' or 5'-GAGGGG-3' sequences.^[1] ^[2]

Publication Abstract from PubMed

SMYD3 is a lysine methyltransferase overexpressed in colorectal, breast, prostate, and hepatocellular tumors, and has been implicated as an oncogene in human malignancies. Methylation of MEKK2 by SMYD3 is important for regulation of the MEK/ERK pathway, suggesting the possibility of selectively targeting SMYD3 in RAS-driven cancers. Structural and kinetic characterization of SMYD3 was undertaken leading to a co-crystal structure of SMYD3 with a MEKK2-peptide substrate bound, and the observation that SMYD3 follows a partially processive mechanism. These insights allowed for the design of GSK2807, a potent and selective, SAM-competitive inhibitor of SMYD3 (Ki = 14 nM). A high-resolution crystal structure reveals that GSK2807 bridges the gap between the SAM-binding pocket and the substrate lysine tunnel of SMYD3. Taken together, our data demonstrate that small-molecule inhibitors of SMYD3 can be designed to prevent methylation of MEKK2 and these could have potential use as anticancer therapeutics.

Structure-Based Design of a Novel SMYD3 Inhibitor that Bridges the SAM-and MEKK2-Binding Pockets.,Van Aller GS, Graves AP, Elkins PA, Bonnette WG, McDevitt PJ, Zappacosta F, Annan RS, Dean TW, Su DS, Carpenter CL, Mohammad HP, Kruger RG Structure. 2016 May 3;24(5):774-81. doi: 10.1016/j.str.2016.03.010. Epub 2016 Apr, 7. PMID:27066749^[3]

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

References

↑ Hamamoto R, Furukawa Y, Morita M, Iimura Y, Silva FP, Li M, Yagyu R, Nakamura Y. SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nat Cell Biol. 2004 Aug;6(8):731-40. Epub 2004 Jul 4. PMID:15235609 doi:10.1038/ncb1151
↑ Van Aller GS, Reynoird N, Barbash O, Huddleston M, Liu S, Zmoos AF, McDevitt P, Sinnamon R, Le B, Mas G, Annan R, Sage J, Garcia BA, Tummino PJ, Gozani O, Kruger RG. Smyd3 regulates cancer cell phenotypes and catalyzes histone H4 lysine 5 methylation. Epigenetics. 2012 Apr;7(4):340-3. doi: 10.4161/epi.19506. Epub 2012 Apr 1. PMID:22419068 doi:10.4161/epi.19506
↑ Van Aller GS, Graves AP, Elkins PA, Bonnette WG, McDevitt PJ, Zappacosta F, Annan RS, Dean TW, Su DS, Carpenter CL, Mohammad HP, Kruger RG. Structure-Based Design of a Novel SMYD3 Inhibitor that Bridges the SAM-and MEKK2-Binding Pockets. Structure. 2016 May 3;24(5):774-81. doi: 10.1016/j.str.2016.03.010. Epub 2016 Apr, 7. PMID:27066749 doi:http://dx.doi.org/10.1016/j.str.2016.03.010

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5hq8"

@@ Line 1: / Line 1: @@
 ==Co-crystal Structure of human SMYD3 with a MEKK2 peptide at 2.13A==
-<StructureSection load='5hq8' size='340' side='right' caption='[[5hq8]], [[Resolution|resolution]] 1.72&Aring;' scene=''>
+<StructureSection load='5hq8' size='340' side='right'caption='[[5hq8]], [[Resolution|resolution]] 1.72&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5hq8]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HQ8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5HQ8 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5hq8]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HQ8 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5HQ8 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
 <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=NH2:AMINO+GROUP'>NH2</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SMYD3, ZMYND1, ZNFN3A1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5hq8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hq8 OCA], [http://pdbe.org/5hq8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5hq8 RCSB], [http://www.ebi.ac.uk/pdbsum/5hq8 PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5hq8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hq8 OCA], [http://pdbe.org/5hq8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5hq8 RCSB], [http://www.ebi.ac.uk/pdbsum/5hq8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5hq8 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 5hq8" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Histone methyltransferase 3D structures|Histone methyltransferase 3D structures]]
 == References ==
 <references/>
@@ Line 25: / Line 29: @@
 </StructureSection>
 [[Category: Histone-lysine N-methyltransferase]]
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Bonnette, W G]]
 [[Category: Elkins, P A]]

5hq8

From Proteopedia

Revision as of 08:27, 27 May 2020

Co-crystal Structure of human SMYD3 with a MEKK2 peptide at 2.13A

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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