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==Design, synthesis, and biological evaluation of potent and selective Class IIa HDAC inhibitors as a potential therapy for Huntington's disease==
<StructureSection load='4cbt' size='340' side='right'caption='[[4cbt]], [[Resolution|resolution]] 3.03&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4cbt]] is a 3 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=4CBT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4CBT 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]] 3.03&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9F4:(1R,2R,3R)-2-[4-(5-FLUORANYLPYRIMIDIN-2-YL)PHENYL]-N-OXIDANYL-3-PHENYL-CYCLOPROPANE-1-CARBOXAMIDE'>9F4</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=4cbt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cbt OCA], [https://pdbe.org/4cbt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4cbt RCSB], [https://www.ebi.ac.uk/pdbsum/4cbt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4cbt ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/HDAC4_HUMAN HDAC4_HUMAN] Defects in HDAC4 are the cause of brachydactyly-mental retardation syndrome (BDMR) [MIM:[https://omim.org/entry/600430 600430]. A syndrome resembling the physical anomalies found in Albright hereditary osteodystrophy. Common features are mild facial dysmorphism, congenital heart defects, distinct brachydactyly type E, mental retardation, developmental delay, seizures, autism spectrum disorder, and stocky build. Soft tissue ossification is absent, and there are no abnormalities in parathyroid hormone or calcium metabolism.<ref>PMID:20691407</ref> 
== Function ==
[https://www.uniprot.org/uniprot/HDAC4_HUMAN HDAC4_HUMAN] Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation via its interaction with the myocyte enhancer factors such as MEF2A, MEF2C and MEF2D.<ref>PMID:10523670</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Inhibition of Class IIa HDAC enzymes have been suggested as a therapeutic strategy for a number of diseases, including Huntington's disease. Catalytic-site small molecule inhibitors of the Class IIa histone deacetylases HDAC4, 5, 7 and 9 were developed. These trisubstituted diaryl cyclopropane hydroxamic acids were designed to exploit a lower pocket that is characteristic for the Class IIa HDACs, not present in other HDAC classes. Selected inhibitors were co-crystallized with the catalytic domain of human HDAC4. We describe the first HDAC4 catalytic domain crystal structure in a 'closed-loop' form, which in our view represents the biologically relevant conformation. We have demonstrated that these molecules can differentiate Class IIa HDACs from Class I and Class IIb subtypes. They exhibited pharmacokinetic properties that should enable the assessment of their therapeutic benefit in both peripheral and CNS disorders. These selective inhibitors provide a means for evaluating potential efficacy in preclinical models in vivo.

Design, synthesis, and biological evaluation of potent and selective Class IIa histone deacetylase (HDAC) inhibitors as a potential therapy for Huntington's disease.,Burli RW, Luckhurst CA, Aziz O, Matthews KL, Yates D, Lyons KA, Beconi M, McAllister G, Breccia P, Stott AJ, Penrose SD, Wall M, Lamers MB, Leonard P, Mueller I, Richardson CM, Jarvis R, Stones L, Hughes S, Wishart G, Haughan AF, O'Connell C, Mead T, McNeil H, Vann J, Mangette J, Maillard M, Beaumont V, Munoz-Sanjuan I, Dominguez C J Med Chem. 2013 Nov 21. PMID:24261862<ref>PMID:24261862</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4cbt" style="background-color:#fffaf0;"></div>

==See Also==
*[[Histone deacetylase 3D structures|Histone deacetylase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Aziz O]]
[[Category: Beaumont V]]
[[Category: Beconi M]]
[[Category: Breccia P]]
[[Category: Burli RW]]
[[Category: Dominguez C]]
[[Category: Haughan AF]]
[[Category: Hughes S]]
[[Category: Jarvis R]]
[[Category: Lamers M]]
[[Category: Leonard P]]
[[Category: Luckhurst CA]]
[[Category: Lyons KA]]
[[Category: Maillard M]]
[[Category: Mangette J]]
[[Category: Matthews KL]]
[[Category: McAllister G]]
[[Category: McNeil H]]
[[Category: Mead T]]
[[Category: Mueller I]]
[[Category: Munoz-Sanjuan I]]
[[Category: O'Connell C]]
[[Category: Penrose SD]]
[[Category: Richardson CM]]
[[Category: Stones L]]
[[Category: Stott AJ]]
[[Category: Vann J]]
[[Category: Wall M]]
[[Category: Wishart G]]
[[Category: Yates D]]