4cbt

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

spinqualitylabelsall models 4cbt, resolution 3.03Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D 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: 9F4, ZN 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. 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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