View source for 4jlg


==SETD7 in complex with inhibitor (R)-PFI-2 and S-adenosyl-methionine==
<StructureSection load='4jlg' size='340' side='right'caption='[[4jlg]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4jlg]] 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=4JLG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JLG FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.896&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1L8:8-FLUORO-N-{(2R)-1-OXO-1-(PYRROLIDIN-1-YL)-3-[3-(TRIFLUOROMETHYL)PHENYL]PROPAN-2-YL}-1,2,3,4-TETRAHYDROISOQUINOLINE-6-SULFONAMIDE'>1L8</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</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=4jlg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jlg OCA], [https://pdbe.org/4jlg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jlg RCSB], [https://www.ebi.ac.uk/pdbsum/4jlg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jlg ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/SETD7_HUMAN SETD7_HUMAN] Histone methyltransferase that specifically monomethylates 'Lys-4' of histone H3. H3 'Lys-4' methylation represents a specific tag for epigenetic transcriptional activation. Plays a central role in the transcriptional activation of genes such as collagenase or insulin. Recruited by IPF1/PDX-1 to the insulin promoter, leading to activate transcription. Has also methyltransferase activity toward non-histone proteins such as p53/TP53, TAF10, and possibly TAF7 by recognizing and binding the [KR]-[STA]-K in substrate proteins. Monomethylates 'Lys-189' of TAF10, leading to increase the affinity of TAF10 for RNA polymerase II. Monomethylates 'Lys-372' of p53/TP53, stabilizing p53/TP53 and increasing p53/TP53-mediated transcriptional activation.<ref>PMID:12588998</ref> <ref>PMID:15099517</ref> <ref>PMID:16141209</ref> <ref>PMID:17108971</ref> <ref>PMID:12540855</ref> <ref>PMID:15525938</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
SET domain containing (lysine methyltransferase) 7 (SETD7) is implicated in multiple signaling and disease related pathways with a broad diversity of reported substrates. Here, we report the discovery of (R)-PFI-2-a first-in-class, potent (Ki (app) = 0.33 nM), selective, and cell-active inhibitor of the methyltransferase activity of human SETD7-and its 500-fold less active enantiomer, (S)-PFI-2. (R)-PFI-2 exhibits an unusual cofactor-dependent and substrate-competitive inhibitory mechanism by occupying the substrate peptide binding groove of SETD7, including the catalytic lysine-binding channel, and by making direct contact with the donor methyl group of the cofactor, S-adenosylmethionine. Chemoproteomics experiments using a biotinylated derivative of (R)-PFI-2 demonstrated dose-dependent competition for binding to endogenous SETD7 in MCF7 cells pretreated with (R)-PFI-2. In murine embryonic fibroblasts, (R)-PFI-2 treatment phenocopied the effects of Setd7 deficiency on Hippo pathway signaling, via modulation of the transcriptional coactivator Yes-associated protein (YAP) and regulation of YAP target genes. In confluent MCF7 cells, (R)-PFI-2 rapidly altered YAP localization, suggesting continuous and dynamic regulation of YAP by the methyltransferase activity of SETD7. These data establish (R)-PFI-2 and related compounds as a valuable tool-kit for the study of the diverse roles of SETD7 in cells and further validate protein methyltransferases as a druggable target class.

(R)-PFI-2 is a potent and selective inhibitor of SETD7 methyltransferase activity in cells.,Barsyte-Lovejoy D, Li F, Oudhoff MJ, Tatlock JH, Dong A, Zeng H, Wu H, Freeman SA, Schapira M, Senisterra GA, Kuznetsova E, Marcellus R, Allali-Hassani A, Kennedy S, Lambert JP, Couzens AL, Aman A, Gingras AC, Al-Awar R, Fish PV, Gerstenberger BS, Roberts L, Benn CL, Grimley RL, Braam MJ, Rossi FM, Sudol M, Brown PJ, Bunnage ME, Owen DR, Zaph C, Vedadi M, Arrowsmith CH Proc Natl Acad Sci U S A. 2014 Sep 2;111(35):12853-8. doi:, 10.1073/pnas.1407358111. Epub 2014 Aug 18. PMID:25136132<ref>PMID:25136132</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4jlg" style="background-color:#fffaf0;"></div>

==See Also==
*[[Histone methyltransferase 3D structures|Histone methyltransferase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Arrowsmith CH]]
[[Category: Barsyte D]]
[[Category: Bountra C]]
[[Category: Brown PJ]]
[[Category: Bunnage M]]
[[Category: Dong A]]
[[Category: Edwards AM]]
[[Category: El Bakkouri M]]
[[Category: Owen D]]
[[Category: Tatlock J]]
[[Category: Vedadi M]]
[[Category: Wu H]]
[[Category: Zeng H]]