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4cbt

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Revision as of 17:02, 4 August 2016

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

Structural highlights

4cbt is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	4cby
Activity:	Histone deacetylase, with EC number 3.5.1.98
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[HDAC4_HUMAN] Defects in HDAC4 are the cause of brachydactyly-mental retardation syndrome (BDMR) [MIM: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.^[1]

Function

[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.^[2]

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^[3]

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

References

↑ Williams SR, Aldred MA, Der Kaloustian VM, Halal F, Gowans G, McLeod DR, Zondag S, Toriello HV, Magenis RE, Elsea SH. Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems. Am J Hum Genet. 2010 Aug 13;87(2):219-28. doi: 10.1016/j.ajhg.2010.07.011. PMID:20691407 doi:10.1016/j.ajhg.2010.07.011
↑ Wang AH, Bertos NR, Vezmar M, Pelletier N, Crosato M, Heng HH, Th'ng J, Han J, Yang XJ. HDAC4, a human histone deacetylase related to yeast HDA1, is a transcriptional corepressor. Mol Cell Biol. 1999 Nov;19(11):7816-27. PMID:10523670
↑ 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. Design, synthesis, and biological evaluation of potent and selective Class IIa histone deacetylase (HDAC) inhibitors as a potential therapy for Huntington's disease. J Med Chem. 2013 Nov 21. PMID:24261862 doi:http://dx.doi.org/10.1021/jm4011884

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/4cbt"

@@ Line 1: / Line 1: @@
 ==Design, synthesis, and biological evaluation of potent and selective Class IIa HDAC inhibitors as a potential therapy for Huntingtons disease==
 <StructureSection load='4cbt' size='340' side='right' caption='[[4cbt]], [[Resolution|resolution]] 3.03&Aring;' scene=''>
@@ Line 6: / Line 7: @@
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4cby|4cby]]</td></tr>
 <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>
-<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>
+<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://pdbe.org/4cbt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4cbt RCSB], [http://www.ebi.ac.uk/pdbsum/4cbt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4cbt ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 20: / Line 21: @@
 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==

4cbt

From Proteopedia

Revision as of 17:02, 4 August 2016

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

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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