4NH8

Correlation between chemotype-dependent binding conformations of HSP90 alpha/beta and isoform selectivity

Summary for 4NH8

• Entry DOI: 10.2210/pdb4nh8/pdb
• Related: 4NH7
• Descriptor: Heat shock protein HSP 90-alpha, 2-fluoro-6-[(3S)-tetrahydrofuran-3-ylamino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide (3 entities in total)
• Functional Keywords: a/b protein, chaperone
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : P07900
• Total number of polymer chains: 1
• Total formula weight: 26582.86

Authors

Ernst, J.T.,Zuccola, H.J. (deposition date: 2013-11-04, release date: 2014-01-15, Last modification date: 2024-02-28)

Primary citation

Ernst, J.T.,Liu, M.,Zuccola, H.,Neubert, T.,Beaumont, K.,Turnbull, A.,Kallel, A.,Vought, B.,Stamos, D.
Correlation between chemotype-dependent binding conformations of HSP90 alpha / beta and isoform selectivity-Implications for the structure-based design of HSP90 alpha / beta selective inhibitors for treating neurodegenerative diseases.
Bioorg.Med.Chem.Lett., 24:204-208, 2014

PubMed Abstract: HSP90 continues to be a target of interest for neurodegeneration indications. Selective knockdown of the HSP90 cytosolic isoforms α and β is sufficient to reduce mutant huntingtin protein levels in vitro. Chemotype-dependent binding conformations of HSP90α/β appear to strongly influence isoform selectivity. The rational design of HSP90α/β inhibitors selective versus the mitochondrial (TRAP1) and endoplasmic reticulum (GRP94) isoforms offers a potential mitigating strategy for mechanism-based toxicities. Better tolerated HSP90 inhibitors would be attractive for targeting chronic neurodegenerative diseases such as Huntington's disease.

PubMed: 24332488
DOI: 10.1016/j.bmcl.2013.11.036

Experimental method

X-RAY DIFFRACTION (1.65 Å)