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5fwj

From Proteopedia

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Current revision

Crystal structure of human JARID1C in complex with KDM5-C49

Structural highlights

5fwj is a 2 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 2.1Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

KDM5C_HUMAN Syndromic X-linked intellectual disability due to JARID1C mutation. The disease is caused by mutations affecting the gene represented in this entry.

Function

KDM5C_HUMAN Histone demethylase that specifically demethylates 'Lys-4' of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-9', H3 'Lys-27', H3 'Lys-36', H3 'Lys-79' or H4 'Lys-20'. Demethylates trimethylated and dimethylated but not monomethylated H3 'Lys-4'. Participates in transcriptional repression of neuronal genes by recruiting histone deacetylases and REST at neuron-restrictive silencer elements. Represses the CLOCK-ARNTL/BMAL1 heterodimer-mediated transcriptional activation of the core clock component PER2 (By similarity).[UniProtKB:P41230]^[1] ^[2] ^[3]

Publication Abstract from PubMed

Members of the KDM5 (also known as JARID1) family are 2-oxoglutarate- and Fe2+-dependent oxygenases that act as histone H3K4 demethylases, thereby regulating cell proliferation and stem cell self-renewal and differentiation. Here we report crystal structures of the catalytic core of the human KDM5B enzyme in complex with three inhibitor chemotypes. These scaffolds exploit several aspects of the KDM5 active site, and their selectivity profiles reflect their hybrid features with respect to the KDM4 and KDM6 families. Whereas GSK-J1, a previously identified KDM6 inhibitor, showed about sevenfold less inhibitory activity toward KDM5B than toward KDM6 proteins, KDM5-C49 displayed 25-100-fold selectivity between KDM5B and KDM6B. The cell-permeable derivative KDM5-C70 had an antiproliferative effect in myeloma cells, leading to genome-wide elevation of H3K4me3 levels. The selective inhibitor GSK467 exploited unique binding modes, but it lacked cellular potency in the myeloma system. Taken together, these structural leads deliver multiple starting points for further rational and selective inhibitor design.

Structural analysis of human KDM5B guides histone demethylase inhibitor development.,Johansson C, Velupillai S, Tumber A, Szykowska A, Hookway ES, Nowak RP, Strain-Damerell C, Gileadi C, Philpott M, Burgess-Brown N, Wu N, Kopec J, Nuzzi A, Steuber H, Egner U, Badock V, Munro S, LaThangue NB, Westaway S, Brown J, Athanasou N, Prinjha R, Brennan PE, Oppermann U Nat Chem Biol. 2016 May 23. doi: 10.1038/nchembio.2087. PMID:27214403^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Iwase S, Lan F, Bayliss P, de la Torre-Ubieta L, Huarte M, Qi HH, Whetstine JR, Bonni A, Roberts TM, Shi Y. The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. Cell. 2007 Mar 23;128(6):1077-88. Epub 2007 Feb 22. PMID:17320160 doi:10.1016/j.cell.2007.02.017
↑ Christensen J, Agger K, Cloos PA, Pasini D, Rose S, Sennels L, Rappsilber J, Hansen KH, Salcini AE, Helin K. RBP2 belongs to a family of demethylases, specific for tri-and dimethylated lysine 4 on histone 3. Cell. 2007 Mar 23;128(6):1063-76. Epub 2007 Feb 22. PMID:17320161 doi:S0092-8674(07)00182-1
↑ Tahiliani M, Mei P, Fang R, Leonor T, Rutenberg M, Shimizu F, Li J, Rao A, Shi Y. The histone H3K4 demethylase SMCX links REST target genes to X-linked mental retardation. Nature. 2007 May 31;447(7144):601-5. Epub 2007 Apr 29. PMID:17468742 doi:nature05823
↑ Johansson C, Velupillai S, Tumber A, Szykowska A, Hookway ES, Nowak RP, Strain-Damerell C, Gileadi C, Philpott M, Burgess-Brown N, Wu N, Kopec J, Nuzzi A, Steuber H, Egner U, Badock V, Munro S, LaThangue NB, Westaway S, Brown J, Athanasou N, Prinjha R, Brennan PE, Oppermann U. Structural analysis of human KDM5B guides histone demethylase inhibitor development. Nat Chem Biol. 2016 May 23. doi: 10.1038/nchembio.2087. PMID:27214403 doi:http://dx.doi.org/10.1038/nchembio.2087

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5fwj"

@@ Line 3: / Line 3: @@
 <StructureSection load='5fwj' size='340' side='right'caption='[[5fwj]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5fwj]] 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=5FWJ OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5FWJ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5fwj]] 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=5FWJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5FWJ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=MMK:2-{[(2-{[(E)-2-(DIMETHYLAMINO)ETHENYL](ETHYL)AMINO}-2-OXOETHYL)AMINO]METHYL}PYRIDINE-4-CARBOXYLIC+ACID'>MMK</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</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]] 2.1&#8491;</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5fwj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fwj OCA], [http://pdbe.org/5fwj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5fwj RCSB], [http://www.ebi.ac.uk/pdbsum/5fwj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5fwj ProSAT]</span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=MMK:2-{[(2-{[(E)-2-(DIMETHYLAMINO)ETHENYL](ETHYL)AMINO}-2-OXOETHYL)AMINO]METHYL}PYRIDINE-4-CARBOXYLIC+ACID'>MMK</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</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'>[https://proteopedia.org/fgij/fg.htm?mol=5fwj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fwj OCA], [https://pdbe.org/5fwj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5fwj RCSB], [https://www.ebi.ac.uk/pdbsum/5fwj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5fwj ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[http://www.uniprot.org/uniprot/KDM5C_HUMAN KDM5C_HUMAN]] Syndromic X-linked intellectual disability due to JARID1C mutation. The disease is caused by mutations affecting the gene represented in this entry.
+[https://www.uniprot.org/uniprot/KDM5C_HUMAN KDM5C_HUMAN] Syndromic X-linked intellectual disability due to JARID1C mutation. The disease is caused by mutations affecting the gene represented in this entry.
 == Function ==
-[[http://www.uniprot.org/uniprot/KDM5C_HUMAN KDM5C_HUMAN]] Histone demethylase that specifically demethylates 'Lys-4' of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-9', H3 'Lys-27', H3 'Lys-36', H3 'Lys-79' or H4 'Lys-20'. Demethylates trimethylated and dimethylated but not monomethylated H3 'Lys-4'. Participates in transcriptional repression of neuronal genes by recruiting histone deacetylases and REST at neuron-restrictive silencer elements. Represses the CLOCK-ARNTL/BMAL1 heterodimer-mediated transcriptional activation of the core clock component PER2 (By similarity).[UniProtKB:P41230]<ref>PMID:17320160</ref> <ref>PMID:17320161</ref> <ref>PMID:17468742</ref>
+[https://www.uniprot.org/uniprot/KDM5C_HUMAN KDM5C_HUMAN] Histone demethylase that specifically demethylates 'Lys-4' of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-9', H3 'Lys-27', H3 'Lys-36', H3 'Lys-79' or H4 'Lys-20'. Demethylates trimethylated and dimethylated but not monomethylated H3 'Lys-4'. Participates in transcriptional repression of neuronal genes by recruiting histone deacetylases and REST at neuron-restrictive silencer elements. Represses the CLOCK-ARNTL/BMAL1 heterodimer-mediated transcriptional activation of the core clock component PER2 (By similarity).[UniProtKB:P41230]<ref>PMID:17320160</ref> <ref>PMID:17320161</ref> <ref>PMID:17468742</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 27: / Line 28: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Arrowsmith, C H]]
+[[Category: Arrowsmith CH]]
-[[Category: Bountra, C]]
+[[Category: Bountra C]]
-[[Category: Burgess-Brown, N A]]
+[[Category: Burgess-Brown NA]]
-[[Category: Delft, F von]]
+[[Category: Dong W]]
-[[Category: Dong, W]]
+[[Category: Edwards A]]
-[[Category: Edwards, A]]
+[[Category: Gileadi C]]
-[[Category: Gileadi, C]]
+[[Category: Huber K]]
-[[Category: Huber, K]]
+[[Category: Johansson C]]
-[[Category: Johansson, C]]
+[[Category: Kopec J]]
-[[Category: Kopec, J]]
+[[Category: Kupinska K]]
-[[Category: Kupinska, K]]
+[[Category: Nowak R]]
-[[Category: Nowak, R]]
+[[Category: Oppermann U]]
-[[Category: Oppermann, U]]
+[[Category: Shrestha L]]
-[[Category: Shrestha, L]]
+[[Category: Srikannathasan V]]
-[[Category: Srikannathasan, V]]
+[[Category: Strain-Damerell C]]
-[[Category: Strain-Damerell, C]]
+[[Category: Szykowska A]]
-[[Category: Szykowska, A]]
+[[Category: Von Delft F]]
-[[Category: Lysine-specific]]
-[[Category: Lysine-specific demethylase 5c]]
-[[Category: Oxidoreductase]]

5fwj

From Proteopedia

Current revision

Crystal structure of human JARID1C in complex with KDM5-C49

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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