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| | <StructureSection load='6nm4' size='340' side='right'caption='[[6nm4]], [[Resolution|resolution]] 2.58Å' scene=''> | | <StructureSection load='6nm4' size='340' side='right'caption='[[6nm4]], [[Resolution|resolution]] 2.58Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6nm4]] 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=6NM4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6NM4 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6nm4]] 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=6NM4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6NM4 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=KS7:4-[3-(3,5-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-methyl-9-(2-methylpyridin-4-yl)-1,4,9-triazaspiro[5.5]undecane'>KS7</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</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]] 2.58Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PRDM9, PFM6 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=KS7:4-[3-(3,5-dimethoxyphenyl)-1,2,4-oxadiazol-5-yl]-1-methyl-9-(2-methylpyridin-4-yl)-1,4,9-triazaspiro[5.5]undecane'>KS7</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene>, <scene name='pdbligand=UNX:UNKNOWN+ATOM+OR+ION'>UNX</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'>[https://proteopedia.org/fgij/fg.htm?mol=6nm4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nm4 OCA], [https://pdbe.org/6nm4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6nm4 RCSB], [https://www.ebi.ac.uk/pdbsum/6nm4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6nm4 ProSAT]</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=6nm4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nm4 OCA], [http://pdbe.org/6nm4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6nm4 RCSB], [http://www.ebi.ac.uk/pdbsum/6nm4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6nm4 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PRDM9_HUMAN PRDM9_HUMAN]] Histone methyltransferase that specifically trimethylates 'Lys-4' of histone H3 during meiotic prophase and is essential for proper meiotic progression. Does not have the ability to mono- and dimethylate '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 during early meiotic prophase (By similarity). | + | [https://www.uniprot.org/uniprot/PRDM9_HUMAN PRDM9_HUMAN] Histone methyltransferase that specifically trimethylates 'Lys-4' of histone H3 during meiotic prophase and is essential for proper meiotic progression. Does not have the ability to mono- and dimethylate '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 during early meiotic prophase (By similarity). |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Histone-lysine N-methyltransferase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Arrowsmith, C H]] | + | [[Category: Arrowsmith CH]] |
| - | [[Category: Bountra, C]] | + | [[Category: Bountra C]] |
| - | [[Category: Brown, P J]] | + | [[Category: Brown PJ]] |
| - | [[Category: Edwards, A M]] | + | [[Category: Edwards AM]] |
| - | [[Category: Fischer, C]] | + | [[Category: Fischer C]] |
| - | [[Category: Halabelian, L]] | + | [[Category: Halabelian L]] |
| - | [[Category: Ivanochko, D]] | + | [[Category: Ivanochko D]] |
| - | [[Category: Kattar, S D]] | + | [[Category: Kattar SD]] |
| - | [[Category: Structural genomic]]
| + | [[Category: Sanders JM]] |
| - | [[Category: Sanders, J M]] | + | |
| - | [[Category: Gene regulation-inhibitor complex]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Lysine methyltransferase]]
| + | |
| - | [[Category: Pr set domain]]
| + | |
| - | [[Category: Sgc]]
| + | |
| Structural highlights
Function
PRDM9_HUMAN Histone methyltransferase that specifically trimethylates 'Lys-4' of histone H3 during meiotic prophase and is essential for proper meiotic progression. Does not have the ability to mono- and dimethylate '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 during early meiotic prophase (By similarity).
Publication Abstract from PubMed
PRDM9 is a PR domain containing protein which trimethylates histone 3 on lysine 4 and 36. Its normal expression is restricted to germ cells and attenuation of its activity results in altered meiotic gene transcription, impairment of double-stranded breaks and pairing between homologous chromosomes. There is growing evidence for a role of aberrant expression of PRDM9 in oncogenesis and genome instability. Here we report the discovery of MRK-740, a potent (IC50: 80 +/- 16 nM), selective and cell-active PRDM9 inhibitor (Chemical Probe). MRK-740 binds in the substrate-binding pocket, with unusually extensive interactions with the cofactor S-adenosylmethionine (SAM), conferring SAM-dependent substrate-competitive inhibition. In cells, MRK-740 specifically and directly inhibits H3K4 methylation at endogenous PRDM9 target loci, whereas the closely related inactive control compound, MRK-740-NC, does not. The discovery of MRK-740 as a chemical probe for the PRDM subfamily of methyltransferases highlights the potential for exploiting SAM in targeting SAM-dependent methyltransferases.
Discovery of a chemical probe for PRDM9.,Allali-Hassani A, Szewczyk MM, Ivanochko D, Organ SL, Bok J, Ho JSY, Gay FPH, Li F, Blazer L, Eram MS, Halabelian L, Dilworth D, Luciani GM, Lima-Fernandes E, Wu Q, Loppnau P, Palmer N, Talib SZA, Brown PJ, Schapira M, Kaldis P, O'Hagan RC, Guccione E, Barsyte-Lovejoy D, Arrowsmith CH, Sanders JM, Kattar SD, Bennett DJ, Nicholson B, Vedadi M Nat Commun. 2019 Dec 17;10(1):5759. doi: 10.1038/s41467-019-13652-x. PMID:31848333[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Allali-Hassani A, Szewczyk MM, Ivanochko D, Organ SL, Bok J, Ho JSY, Gay FPH, Li F, Blazer L, Eram MS, Halabelian L, Dilworth D, Luciani GM, Lima-Fernandes E, Wu Q, Loppnau P, Palmer N, Talib SZA, Brown PJ, Schapira M, Kaldis P, O'Hagan RC, Guccione E, Barsyte-Lovejoy D, Arrowsmith CH, Sanders JM, Kattar SD, Bennett DJ, Nicholson B, Vedadi M. Discovery of a chemical probe for PRDM9. Nat Commun. 2019 Dec 17;10(1):5759. doi: 10.1038/s41467-019-13652-x. PMID:31848333 doi:http://dx.doi.org/10.1038/s41467-019-13652-x
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