3s7b: Difference between revisions

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<StructureSection load='3s7b' size='340' side='right'caption='[[3s7b]], [[Resolution|resolution]] 2.42&Aring;' scene=''>
<StructureSection load='3s7b' size='340' side='right'caption='[[3s7b]], [[Resolution|resolution]] 2.42&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3s7b]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S7B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3S7B FirstGlance]. <br>
<table><tr><td colspan='2'>[[3s7b]] is a 1 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=3S7B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3S7B FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BU3:(R,R)-2,3-BUTANEDIOL'>BU3</scene>, <scene name='pdbligand=NH5:N-CYCLOHEXYL-N~3~-[2-(3,4-DICHLOROPHENYL)ETHYL]-N-(2-{[2-(5-HYDROXY-3-OXO-3,4-DIHYDRO-2H-1,4-BENZOXAZIN-8-YL)ETHYL]AMINO}ETHYL)-BETA-ALANINAMIDE'>NH5</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 2.42&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3s7d|3s7d]], [[3s7f|3s7f]], [[3s7j|3s7j]]</div></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BU3:(R,R)-2,3-BUTANEDIOL'>BU3</scene>, <scene name='pdbligand=NH5:N-CYCLOHEXYL-N~3~-[2-(3,4-DICHLOROPHENYL)ETHYL]-N-(2-{[2-(5-HYDROXY-3-OXO-3,4-DIHYDRO-2H-1,4-BENZOXAZIN-8-YL)ETHYL]AMINO}ETHYL)-BETA-ALANINAMIDE'>NH5</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SMYD2, KMT3C ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=3s7b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s7b OCA], [https://pdbe.org/3s7b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3s7b RCSB], [https://www.ebi.ac.uk/pdbsum/3s7b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3s7b ProSAT]</span></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=3s7b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s7b OCA], [https://pdbe.org/3s7b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3s7b RCSB], [https://www.ebi.ac.uk/pdbsum/3s7b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3s7b ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[https://www.uniprot.org/uniprot/SMYD2_HUMAN SMYD2_HUMAN]] Protein-lysine N-methyltransferase that methylates both histones and non-histone proteins. Specifically methylates histone H3 'Lys-4' (H3K4me) and dimethylates histone H3 'Lys-36' (H3K36me2). Has also methyltransferase activity toward non-histone proteins such as p53/TP53 and RB1. Monomethylates 'Lys-370' of p53/TP53, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity of p53/TP53. Monomethylates 'Lys-860' of RB1/RB.<ref>PMID:17108971</ref> <ref>PMID:17805299</ref> <ref>PMID:18065756</ref> <ref>PMID:20870719</ref> 
[https://www.uniprot.org/uniprot/SMYD2_HUMAN SMYD2_HUMAN] Protein-lysine N-methyltransferase that methylates both histones and non-histone proteins. Specifically methylates histone H3 'Lys-4' (H3K4me) and dimethylates histone H3 'Lys-36' (H3K36me2). Has also methyltransferase activity toward non-histone proteins such as p53/TP53 and RB1. Monomethylates 'Lys-370' of p53/TP53, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity of p53/TP53. Monomethylates 'Lys-860' of RB1/RB.<ref>PMID:17108971</ref> <ref>PMID:17805299</ref> <ref>PMID:18065756</ref> <ref>PMID:20870719</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Protein lysine methyltransferases are important regulators of epigenetic signaling. These enzymes catalyze the transfer of donor methyl groups from S-adenosylmethionine to specific acceptor lysines on histones, leading to changes in chromatin structure and transcriptional regulation. These enzymes also methylate nonhistone protein substrates, revealing an additional mechanism to regulate cellular physiology. The oncogenic protein SMYD2 represses the functional activities of the tumor suppressor proteins p53 and Rb, making it an attractive drug target. Here we report the discovery of AZ505, a potent and selective inhibitor of SMYD2 that was identified from a high throughput chemical screen. We also present the crystal structures of SMYD2 with p53 substrate and product peptides, and notably, in complex with AZ505. This substrate competitive inhibitor is bound in the peptide binding groove of SMYD2. These results have implications for the development of SMYD2 inhibitors, and indicate the potential for developing novel therapies targeting this target class.
 
Structural Basis of Substrate Methylation and Inhibition of SMYD2.,Ferguson AD, Larsen NA, Howard T, Pollard H, Green I, Grande C, Cheung T, Garcia-Arenas R, Cowen S, Wu J, Godin R, Chen H, Keen N Structure. 2011 Jul 20. PMID:21782458<ref>PMID:21782458</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3s7b" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Ferguson, A D]]
[[Category: Ferguson AD]]
[[Category: Methyltransferase]]
[[Category: Transferase]]

Latest revision as of 12:48, 1 March 2024

Structural Basis of Substrate Methylation and Inhibition of SMYD2Structural Basis of Substrate Methylation and Inhibition of SMYD2

Structural highlights

3s7b is a 1 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 2.42Å
Ligands:, , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

SMYD2_HUMAN Protein-lysine N-methyltransferase that methylates both histones and non-histone proteins. Specifically methylates histone H3 'Lys-4' (H3K4me) and dimethylates histone H3 'Lys-36' (H3K36me2). Has also methyltransferase activity toward non-histone proteins such as p53/TP53 and RB1. Monomethylates 'Lys-370' of p53/TP53, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity of p53/TP53. Monomethylates 'Lys-860' of RB1/RB.[1] [2] [3] [4]

See Also

References

  1. ↑ Huang J, Perez-Burgos L, Placek BJ, Sengupta R, Richter M, Dorsey JA, Kubicek S, Opravil S, Jenuwein T, Berger SL. Repression of p53 activity by Smyd2-mediated methylation. Nature. 2006 Nov 30;444(7119):629-32. Epub 2006 Nov 15. PMID:17108971 doi:10.1038/nature05287
  2. ↑ Huang J, Sengupta R, Espejo AB, Lee MG, Dorsey JA, Richter M, Opravil S, Shiekhattar R, Bedford MT, Jenuwein T, Berger SL. p53 is regulated by the lysine demethylase LSD1. Nature. 2007 Sep 6;449(7158):105-8. PMID:17805299 doi:nature06092
  3. ↑ Abu-Farha M, Lambert JP, Al-Madhoun AS, Elisma F, Skerjanc IS, Figeys D. The tale of two domains: proteomics and genomics analysis of SMYD2, a new histone methyltransferase. Mol Cell Proteomics. 2008 Mar;7(3):560-72. Epub 2007 Dec 7. PMID:18065756 doi:10.1074/mcp.M700271-MCP200
  4. ↑ Saddic LA, West LE, Aslanian A, Yates JR 3rd, Rubin SM, Gozani O, Sage J. Methylation of the retinoblastoma tumor suppressor by SMYD2. J Biol Chem. 2010 Nov 26;285(48):37733-40. doi: 10.1074/jbc.M110.137612. Epub, 2010 Sep 24. PMID:20870719 doi:10.1074/jbc.M110.137612

3s7b, resolution 2.42Å

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