View source for 6h51


==Crystal structure of human KDM5B in complex with compound 34f==
<StructureSection load='6h51' size='340' side='right'caption='[[6h51]], [[Resolution|resolution]] 2.21&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6h51]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6H51 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6H51 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FQK:8-[4-[1-(cyclobutylmethyl)piperidin-4-yl]pyrazol-1-yl]-3~{H}-pyrido[3,4-d]pyrimidin-4-one'>FQK</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=6h51 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6h51 OCA], [http://pdbe.org/6h51 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6h51 RCSB], [http://www.ebi.ac.uk/pdbsum/6h51 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6h51 ProSAT]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/KDM5B_HUMAN KDM5B_HUMAN]] Histone demethylase that demethylates 'Lys-4' of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-9' or H3 'Lys-27'. Demethylates trimethylated, dimethylated and monomethylated H3 'Lys-4'. Acts as a transcriptional corepressor for FOXG1B and PAX9. Favors the proliferation of breast cancer cells by repressing tumor suppressor genes such as BRCA1 and HOXA5. In contrast, may act as a tumor suppressor for melanoma.<ref>PMID:12657635</ref> <ref>PMID:16645588</ref> <ref>PMID:17320161</ref> <ref>PMID:17363312</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Residues in the histone substrate binding sites that differ between the KDM4 and KDM5 subfamilies were identified. Subsequently, a C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one series was designed to rationally exploit these residue differences between the histone substrate binding sites in order to improve affinity for the KDM4-subfamily over KDM5-subfamily enzymes. In particular, residues E169 and V313 (KDM4A numbering) were targeted. Additionally, conformational restriction of the flexible pyridopyrimidinone C8-substituent was investigated. These approaches yielded potent and cell-penetrant dual KDM4/5-subfamily inhibitors including 19a (KDM4A and KDM5B Ki=0.004 and 0.007muM, respectively). Compound cellular profiling in two orthogonal target engagement assays revealed a significant reduction from biochemical to cell-based activity across multiple analogues; this decrease was shown to be consistent with 2OG competition, and suggests that sub-nanomolar biochemical potency will be required with C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one compounds to achieve sub-micromolar target inhibition in cells.

C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-ones: Studies towards the identification of potent, cell penetrant Jumonji C domain containing histone lysine demethylase 4 subfamily (KDM4) inhibitors, compound profiling in cell-based target engagement assays.,Le Bihan YV, Lanigan RM, Atrash B, McLaughlin MG, Velupillai S, Malcolm AG, England KS, Ruda GF, Mok NY, Tumber A, Tomlin K, Saville H, Shehu E, McAndrew C, Carmichael L, Bennett JM, Jeganathan F, Eve P, Donovan A, Hayes A, Wood F, Raynaud FI, Fedorov O, Brennan PE, Burke R, van Montfort RLM, Rossanese OW, Blagg J, Bavetsias V Eur J Med Chem. 2019 May 17;177:316-337. doi: 10.1016/j.ejmech.2019.05.041. PMID:31158747<ref>PMID:31158747</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6h51" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Bihan, Y V.Le]]
[[Category: Montfort, R L.M van]]
[[Category: Velupillai, S]]
[[Category: Histone demethylase]]
[[Category: Inhibitor]]
[[Category: Oxidoreductase]]
[[Category: Transcription]]