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| | ==Crystal structure of UTX complexed with 5-hydroxy-4-keto-1-methyl-picolinate== | | ==Crystal structure of UTX complexed with 5-hydroxy-4-keto-1-methyl-picolinate== |
| - | <StructureSection load='6ful' size='340' side='right' caption='[[6ful]], [[Resolution|resolution]] 1.65Å' scene=''> | + | <StructureSection load='6ful' size='340' side='right'caption='[[6ful]], [[Resolution|resolution]] 1.65Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6ful]] is a 1 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=6FUL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FUL FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6ful]] 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=6FUL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6FUL FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=E7Z:1-methyl-5-oxidanyl-4-oxidanylidene-pyridine-2-carboxylic+acid'>E7Z</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=PG0:2-(2-METHOXYETHOXY)ETHANOL'>PG0</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.649Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">KDM6A, UTX ([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=E7Z:1-methyl-5-oxidanyl-4-oxidanylidene-pyridine-2-carboxylic+acid'>E7Z</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=PG0:2-(2-METHOXYETHOXY)ETHANOL'>PG0</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=6ful FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ful OCA], [http://pdbe.org/6ful PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ful RCSB], [http://www.ebi.ac.uk/pdbsum/6ful PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ful 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=6ful FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ful OCA], [https://pdbe.org/6ful PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ful RCSB], [https://www.ebi.ac.uk/pdbsum/6ful PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ful ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/KDM6A_HUMAN KDM6A_HUMAN]] Kabuki syndrome. The disease is caused by mutations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/KDM6A_HUMAN KDM6A_HUMAN] Kabuki syndrome. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/KDM6A_HUMAN KDM6A_HUMAN]] Histone demethylase that specifically demethylates 'Lys-27' of histone H3, thereby playing a central role in histone code. Demethylates trimethylated and dimethylated but not monomethylated H3 'Lys-27'. Plays a central role in regulation of posterior development, by regulating HOX gene expression. Demethylation of 'Lys-27' of histone H3 is concomitant with methylation of 'Lys-4' of histone H3, and regulates the recruitment of the PRC1 complex and monoubiquitination of histone H2A.<ref>PMID:17851529</ref> <ref>PMID:17761849</ref> | + | [https://www.uniprot.org/uniprot/KDM6A_HUMAN KDM6A_HUMAN] Histone demethylase that specifically demethylates 'Lys-27' of histone H3, thereby playing a central role in histone code. Demethylates trimethylated and dimethylated but not monomethylated H3 'Lys-27'. Plays a central role in regulation of posterior development, by regulating HOX gene expression. Demethylation of 'Lys-27' of histone H3 is concomitant with methylation of 'Lys-4' of histone H3, and regulates the recruitment of the PRC1 complex and monoubiquitination of histone H2A.<ref>PMID:17851529</ref> <ref>PMID:17761849</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6ful" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6ful" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Lysine-specific histone demethylase 3D structures|Lysine-specific histone demethylase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Caflisch, A]] | + | [[Category: Large Structures]] |
| - | [[Category: Esposito, C]] | + | [[Category: Caflisch A]] |
| - | [[Category: Sledz, P]] | + | [[Category: Esposito C]] |
| - | [[Category: Inhibitor]] | + | [[Category: Sledz P]] |
| - | [[Category: Jumonji demethylase]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| Structural highlights
6ful 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 1.649Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
KDM6A_HUMAN Kabuki syndrome. The disease is caused by mutations affecting the gene represented in this entry.
Function
KDM6A_HUMAN Histone demethylase that specifically demethylates 'Lys-27' of histone H3, thereby playing a central role in histone code. Demethylates trimethylated and dimethylated but not monomethylated H3 'Lys-27'. Plays a central role in regulation of posterior development, by regulating HOX gene expression. Demethylation of 'Lys-27' of histone H3 is concomitant with methylation of 'Lys-4' of histone H3, and regulates the recruitment of the PRC1 complex and monoubiquitination of histone H2A.[1] [2]
Publication Abstract from PubMed
In the search for new demethylase inhibitors, we have developed a multistep protocol for in silico screening. Millions of poses generated by high-throughput docking or a 3D-pharmacophore search are first minimized by a classical force field and then filtered by semiempirical quantum mechanical calculations of the interaction energy with a selected set of functional groups in the binding site. The final ranking includes solvation effects which are evaluated in the continuum dielectric approximation (finite-difference Poisson equation). Application of the multistep protocol to JMJD3 jumonji demethylase has resulted in a dozen low-micromolar inhibitors belonging to five different chemical classes. We have solved the crystal structure of JMJD3 inhibitor 8 in the complex with UTX (a demethylase in the same subfamily as JMJD3) which validates the predicted binding mode. Compound 8 is a promising candidate for future optimization as it has a favorable ligand efficiency of 0.32 kcal/mol per nonhydrogen atom.
In Silico Identification of JMJD3 Demethylase Inhibitors.,Esposito C, Wiedmer L, Caflisch A J Chem Inf Model. 2018 Oct 3. doi: 10.1021/acs.jcim.8b00539. PMID:30226987[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lan F, Bayliss PE, Rinn JL, Whetstine JR, Wang JK, Chen S, Iwase S, Alpatov R, Issaeva I, Canaani E, Roberts TM, Chang HY, Shi Y. A histone H3 lysine 27 demethylase regulates animal posterior development. Nature. 2007 Oct 11;449(7163):689-94. Epub 2007 Sep 12. PMID:17851529 doi:http://dx.doi.org/10.1038/nature06192
- ↑ Lee MG, Villa R, Trojer P, Norman J, Yan KP, Reinberg D, Di Croce L, Shiekhattar R. Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination. Science. 2007 Oct 19;318(5849):447-50. Epub 2007 Aug 30. PMID:17761849 doi:http://dx.doi.org/1149042
- ↑ Esposito C, Wiedmer L, Caflisch A. In Silico Identification of JMJD3 Demethylase Inhibitors. J Chem Inf Model. 2018 Oct 3. doi: 10.1021/acs.jcim.8b00539. PMID:30226987 doi:http://dx.doi.org/10.1021/acs.jcim.8b00539
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