4NH9

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

Summary for 4NH9

• Entry DOI: 10.2210/pdb4nh9/pdb
• Related: 4NH7 4NH8
• Descriptor: Endoplasmin, 2-fluoro-6-[(3S)-tetrahydrofuran-3-ylamino]-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide (2 entities in total)
• Functional Keywords: a/b structure, chaperone, endoplasmic reticulum
• Biological source: Homo sapiens (human)
• Cellular location: Endoplasmic reticulum lumen: P14625
• Total number of polymer chains: 1
• Total formula weight: 31485.28

Authors

Zuccola, H.J.,Ernst, J.T. (deposition date: 2013-11-04, release date: 2014-01-22, 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 (2.77 Å)