4o07 | pdb_00004o07

Identification of novel HSP90/isoform selective inhibitors using structure-based drug design. Demonstration of potential utility in treating CNS disorders such as Huntington's disease

spinqualitylabelsall models 4o07, resolution 1.86Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4o07 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: FGH Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function HS90A_HUMAN Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function. Publication Abstract from PubMed A structure-based drug design strategy was used to optimize a novel benzolactam series of HSP90alpha/beta inhibitors to achieve >1,000-fold selectivity versus the HSP90 endoplasmic reticulum and mitochondrial isoforms (GRP94 and TRAP1, respectively). Selective HSP90alpha/beta inhibitors were found to be equipotent to pan-HSP90 inhibitors in promoting the clearance of mutant huntingtin protein (mHtt) in vitro, however with less cellular toxicity. Improved tolerability profiles may enable the use of HSP90alpha/beta selective inhibitors in treating chronic neurodegenerative indications such as Huntington's disease (HD). A potent, selective, orally available HSP90alpha/beta inhibitor was identified (compound 31) that crosses the blood brain barrier. Compound 31 demonstrated proof of concept by successfully reducing brain Htt levels following oral dosing in rats. Identification of novel HSP90alpha/beta isoform selective inhibitors using structure-based drug design. Demonstration of potential utility in treating CNS disorders such as Huntington's disease.,Ernst J, Neubert T, Liu M, Sperry S, Zuccola H, Turnbull A, Fleck B, Kargo W, Woody L, Chiang P, Tran D, Chen W, Snyder PW, Alcacio T, Nezami A, Reynolds J, Alvi K, Goulet L, Stamos D J Med Chem. 2014 Mar 27. PMID:24673104 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Heat Shock Protein structures

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