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5th7

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==Complex of SETD8 with MS453==
==Complex of SETD8 with MS453==
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<StructureSection load='5th7' size='340' side='right' caption='[[5th7]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
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<StructureSection load='5th7' size='340' side='right'caption='[[5th7]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5th7]] is a 2 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=5TH7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TH7 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5th7]] is a 2 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=5TH7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TH7 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7BY:N-(3-{[6,7-DIMETHOXY-2-(PYRROLIDIN-1-YL)QUINAZOLIN-4-YL]AMINO}PROPYL)PROPANAMIDE'>7BY</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.95&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">KMT5A, PRSET7, SET07, SET8, SETD8 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7BY:N-(3-{[6,7-DIMETHOXY-2-(PYRROLIDIN-1-YL)QUINAZOLIN-4-YL]AMINO}PROPYL)PROPANAMIDE'>7BY</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</scene></td></tr>
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<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=5th7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5th7 OCA], [http://pdbe.org/5th7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5th7 RCSB], [http://www.ebi.ac.uk/pdbsum/5th7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5th7 ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5th7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5th7 OCA], [https://pdbe.org/5th7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5th7 RCSB], [https://www.ebi.ac.uk/pdbsum/5th7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5th7 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/KMT5A_HUMAN KMT5A_HUMAN]] Protein-lysine N-methyltransferase that monomethylates both histones and non-histone proteins. Specifically monomethylates 'Lys-20' of histone H4 (H4K20me1). H4K20me1 is enriched during mitosis and represents a specific tag for epigenetic transcriptional repression. Mainly functions in euchromatin regions, thereby playing a central role in the silencing of euchromatic genes. Required for cell proliferation, probably by contributing to the maintenance of proper higher-order structure of DNA during mitosis. Involved in chromosome condensation and proper cytokinesis. Nucleosomes are preferred as substrate compared to free histones. Mediates monomethylation of p53/TP53 at 'Lys-382', leading to repress p53/TP53-target genes. Plays a negative role in TGF-beta response regulation and a positive role in cell migration.<ref>PMID:12086618</ref> <ref>PMID:12121615</ref> <ref>PMID:15200950</ref> <ref>PMID:15933069</ref> <ref>PMID:15933070</ref> <ref>PMID:16517599</ref> <ref>PMID:17707234</ref> <ref>PMID:23478445</ref>
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[https://www.uniprot.org/uniprot/KMT5A_HUMAN KMT5A_HUMAN] Protein-lysine N-methyltransferase that monomethylates both histones and non-histone proteins. Specifically monomethylates 'Lys-20' of histone H4 (H4K20me1). H4K20me1 is enriched during mitosis and represents a specific tag for epigenetic transcriptional repression. Mainly functions in euchromatin regions, thereby playing a central role in the silencing of euchromatic genes. Required for cell proliferation, probably by contributing to the maintenance of proper higher-order structure of DNA during mitosis. Involved in chromosome condensation and proper cytokinesis. Nucleosomes are preferred as substrate compared to free histones. Mediates monomethylation of p53/TP53 at 'Lys-382', leading to repress p53/TP53-target genes. Plays a negative role in TGF-beta response regulation and a positive role in cell migration.<ref>PMID:12086618</ref> <ref>PMID:12121615</ref> <ref>PMID:15200950</ref> <ref>PMID:15933069</ref> <ref>PMID:15933070</ref> <ref>PMID:16517599</ref> <ref>PMID:17707234</ref> <ref>PMID:23478445</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Selective inhibitors of protein lysine methyltransferases, including SET domain-containing protein 8 (SETD8), are highly desired, as only a fraction of these enzymes are associated with high-quality inhibitors. From our previously discovered SETD8 inhibitor, we developed a more potent analog and solved a cocrystal structure, which is the first crystal structure of SETD8 in complex with a small-molecule inhibitor. This cocrystal structure allowed the design of a covalent inhibitor of SETD8 (MS453), which specifically modifies a cysteine residue near the inhibitor binding site, has an IC50 value of 804 nM, reacts with SETD8 with near-quantitative yield, and is selective for SETD8 against 28 other methyltransferases. We also solved the crystal structure of the covalent inhibitor in complex with SETD8. This work provides atomic-level perspective on the inhibition of SETD8 by small molecules and will help identify high-quality chemical probes of SETD8.
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Structure-Based Design of a Covalent Inhibitor of the SET Domain-Containing Protein 8 (SETD8) Lysine Methyltransferase.,Butler KV, Ma A, Yu W, Li F, Tempel W, Babault N, Pittella-Silva F, Shao J, Wang J, Luo M, Vedadi M, Brown PJ, Arrowsmith CH, Jin J J Med Chem. 2016 Nov 10;59(21):9881-9889. doi: 10.1021/acs.jmedchem.6b01244. Epub, 2016 Nov 2. PMID:27804297<ref>PMID:27804297</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 5th7" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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*[[Histone methyltransferase|Histone methyltransferase]]
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*[[Histone methyltransferase 3D structures|Histone methyltransferase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
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[[Category: Arrowsmith, C H]]
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[[Category: Large Structures]]
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[[Category: Babault, N]]
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[[Category: Arrowsmith CH]]
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[[Category: Bountra, C]]
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[[Category: Babault N]]
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[[Category: Brown, P J]]
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[[Category: Bountra C]]
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[[Category: Butler, K V]]
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[[Category: Brown PJ]]
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[[Category: Edwards, A M]]
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[[Category: Butler KV]]
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[[Category: Jin, J]]
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[[Category: Edwards AM]]
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[[Category: Ma, A]]
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[[Category: Jin J]]
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[[Category: Structural genomic]]
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[[Category: Ma A]]
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[[Category: Tempel, W]]
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[[Category: Tempel W]]
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[[Category: Yu, W]]
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[[Category: Yu W]]
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[[Category: Sgc]]
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[[Category: Transferase]]
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Current revision

Complex of SETD8 with MS453

PDB ID 5th7

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