View source for 5iw0


==Linked KDM5A Jmj Domain Bound to the Inhibitor N19 [2-(5-((4-chloro-2-methylbenzyl)oxy)-1H-pyrazol-1-yl)isonicotinic acid]==
<StructureSection load='5iw0' size='340' side='right'caption='[[5iw0]], [[Resolution|resolution]] 1.63&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5iw0]] 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=5IW0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5IW0 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]] 1.63&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6EP:2-{5-[(4-CHLORO-2-METHYLPHENYL)METHOXY]-1H-PYRAZOL-1-YL}PYRIDINE-4-CARBOXYLIC+ACID'>6EP</scene>, <scene name='pdbligand=AKG:2-OXOGLUTARIC+ACID'>AKG</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</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=5iw0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5iw0 OCA], [https://pdbe.org/5iw0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5iw0 RCSB], [https://www.ebi.ac.uk/pdbsum/5iw0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5iw0 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/KDM5A_HUMAN KDM5A_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'. May stimulate transcription mediated by nuclear receptors. May be involved in transcriptional regulation of Hox proteins during cell differentiation. May participate in transcriptional repression of cytokines such as CXCL12. Plays a role in the regulation of the circadian rhythm and in maintaining the normal periodicity of the circadian clock. In a histone demethylase-independent manner, acts as a coactivator of the CLOCK-ARNTL/BMAL1-mediated transcriptional activation of PER1/2 and other clock-controlled genes and increases histone acetylation at PER1/2 promoters by inhibiting the activity of HDAC1 (By similarity).[UniProtKB:Q3UXZ9]<ref>PMID:11358960</ref> <ref>PMID:15949438</ref> <ref>PMID:17320160</ref> <ref>PMID:17320161</ref> <ref>PMID:17320163</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The KDM5/JARID1 family of Fe(II)- and alpha-ketoglutarate-dependent demethylases removes methyl groups from methylated lysine 4 of histone H3. Accumulating evidence supports a role for KDM5 family members as oncogenic drivers. We compare the in vitro inhibitory properties and binding affinity of ten diverse compounds with all four family members, and present the crystal structures of the KDM5A-linked Jumonji domain in complex with eight of these inhibitors in the presence of Mn(II). All eight inhibitors structurally examined occupy the binding site of alpha-ketoglutarate, but differ in their specific binding interactions, including the number of ligands involved in metal coordination. We also observed inhibitor-induced conformational changes in KDM5A, particularly those residues involved in the binding of alpha-ketoglutarate, the anticipated peptide substrate, and intramolecular interactions. We discuss how particular chemical moieties contribute to inhibitor potency and suggest strategies that might be utilized in the successful design of selective and potent epigenetic inhibitors.

Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds.,Horton JR, Liu X, Gale M, Wu L, Shanks JR, Zhang X, Webber PJ, Bell JS, Kales SC, Mott BT, Rai G, Jansen DJ, Henderson MJ, Urban DJ, Hall MD, Simeonov A, Maloney DJ, Johns MA, Fu H, Jadhav A, Vertino PM, Yan Q, Cheng X Cell Chem Biol. 2016 Jul 21;23(7):769-81. doi: 10.1016/j.chembiol.2016.06.006., Epub 2016 Jul 14. PMID:27427228<ref>PMID:27427228</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5iw0" style="background-color:#fffaf0;"></div>

==See Also==
*[[Jumonji domain-containing protein 3D structures|Jumonji domain-containing protein 3D structures]]
*[[Lysine-specific histone demethylase 3D structures|Lysine-specific histone demethylase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Cheng X]]
[[Category: Horton JR]]