4cbt

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{{STRUCTURE_4cbt| PDB=4cbt | SCENE= }}
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==Design, synthesis, and biological evaluation of potent and selective Class IIa HDAC inhibitors as a potential therapy for Huntingtons disease==
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===Design, synthesis, and biological evaluation of potent and selective Class IIa HDAC inhibitors as a potential therapy for Huntingtons disease===
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<StructureSection load='4cbt' size='340' side='right' caption='[[4cbt]], [[Resolution|resolution]] 3.03&Aring;' scene=''>
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{{ABSTRACT_PUBMED_24261862}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4cbt]] is a 3 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=4CBT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CBT FirstGlance]. <br>
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==Disease==
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4cby|4cby]]</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Histone_deacetylase Histone deacetylase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.1.98 3.5.1.98] </span></td></tr>
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<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=4cbt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4cbt OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4cbt RCSB], [http://www.ebi.ac.uk/pdbsum/4cbt PDBsum]</span></td></tr>
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</table>
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== Disease ==
[[http://www.uniprot.org/uniprot/HDAC4_HUMAN HDAC4_HUMAN]] Defects in HDAC4 are the cause of brachydactyly-mental retardation syndrome (BDMR) [MIM:[http://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>
[[http://www.uniprot.org/uniprot/HDAC4_HUMAN HDAC4_HUMAN]] Defects in HDAC4 are the cause of brachydactyly-mental retardation syndrome (BDMR) [MIM:[http://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>
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== Function ==
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[[http://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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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==Function==
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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>
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[[http://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>
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[4cbt]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CBT OCA].
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</div>
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==Reference==
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==See Also==
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<ref group="xtra">PMID:024261862</ref><references group="xtra"/><references/>
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*[[Histone deacetylase|Histone deacetylase]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Histone deacetylase]]
[[Category: Histone deacetylase]]
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[[Category: Aziz, O.]]
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[[Category: Human]]
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[[Category: Beaumont, V.]]
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[[Category: Aziz, O]]
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[[Category: Beconi, M.]]
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[[Category: Beaumont, V]]
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[[Category: Breccia, P.]]
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[[Category: Beconi, M]]
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[[Category: Burli, R W.]]
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[[Category: Breccia, P]]
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[[Category: Dominguez, C.]]
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[[Category: Burli, R W]]
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[[Category: Haughan, A F.]]
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[[Category: Dominguez, C]]
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[[Category: Hughes, S.]]
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[[Category: Haughan, A F]]
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[[Category: Jarvis, R.]]
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[[Category: Hughes, S]]
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[[Category: Lamers, M.]]
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[[Category: Jarvis, R]]
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[[Category: Leonard, P.]]
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[[Category: Lamers, M]]
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[[Category: Luckhurst, C A.]]
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[[Category: Leonard, P]]
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[[Category: Lyons, K A.]]
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[[Category: Luckhurst, C A]]
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[[Category: Maillard, M.]]
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[[Category: Lyons, K A]]
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[[Category: Mangette, J.]]
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[[Category: Maillard, M]]
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[[Category: Matthews, K L.]]
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[[Category: Mangette, J]]
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[[Category: McAllister, G.]]
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[[Category: Matthews, K L]]
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[[Category: McNeil, H.]]
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[[Category: McAllister, G]]
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[[Category: Mead, T.]]
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[[Category: McNeil, H]]
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[[Category: Mueller, I.]]
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[[Category: Mead, T]]
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[[Category: Munoz-Sanjuan, I.]]
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[[Category: Mueller, I]]
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[[Category: OConnell, C.]]
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[[Category: Munoz-Sanjuan, I]]
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[[Category: Penrose, S D.]]
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[[Category: OConnell, C]]
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[[Category: Richardson, C M.]]
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[[Category: Penrose, S D]]
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[[Category: Stones, L.]]
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[[Category: Richardson, C M]]
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[[Category: Stott, A J.]]
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[[Category: Stones, L]]
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[[Category: Vann, J.]]
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[[Category: Stott, A J]]
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[[Category: Wall, M.]]
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[[Category: Vann, J]]
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[[Category: Wishart, G.]]
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[[Category: Wall, M]]
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[[Category: Yates, D.]]
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[[Category: Wishart, G]]
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[[Category: Yates, D]]
[[Category: Amyotrophic lateral sclerosis]]
[[Category: Amyotrophic lateral sclerosis]]
[[Category: Class iia histone deacetylase inhibitor]]
[[Category: Class iia histone deacetylase inhibitor]]

Revision as of 16:25, 21 December 2014

Design, synthesis, and biological evaluation of potent and selective Class IIa HDAC inhibitors as a potential therapy for Huntingtons disease

4cbt, resolution 3.03Å

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