5UCJ

Hsp90b N-terminal domain with inhibitors

Summary for 5UCJ

• Entry DOI: 10.2210/pdb5ucj/pdb
• Related: 5UCH 5UCI
• Descriptor: Heat shock protein HSP 90-beta, (5-fluoroisoindolin-2-yl)(4-hydroxy-5-isopropylbenzo[d]isoxazol-7-yl)methanone, DIMETHYL SULFOXIDE, ... (4 entities in total)
• Functional Keywords: hsp90 inhibitor, chaperone-inhibitor complex, chaperone/inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : P08238
• Total number of polymer chains: 4
• Total formula weight: 100161.14

Authors

Peng, S.,Balch, M.,Matts, R.,Deng, J. (deposition date: 2016-12-22, release date: 2018-01-10, Last modification date: 2024-10-23)

Primary citation

Khandelwal, A.,Kent, C.N.,Balch, M.,Peng, S.,Mishra, S.J.,Deng, J.,Day, V.W.,Liu, W.,Subramanian, C.,Cohen, M.,Holzbeierlein, J.M.,Matts, R.,Blagg, B.S.J.
Structure-guided design of an Hsp90 beta N-terminal isoform-selective inhibitor.
Nat Commun, 9:425-425, 2018

PubMed Abstract: The 90 kDa heat shock protein (Hsp90) is a molecular chaperone responsible for folding proteins that are directly associated with cancer progression. Consequently, inhibition of the Hsp90 protein folding machinery results in a combinatorial attack on numerous oncogenic pathways. Seventeen small-molecule inhibitors of Hsp90 have entered clinical trials, all of which bind the Hsp90 N-terminus and exhibit pan-inhibitory activity against all four Hsp90 isoforms. pan-Inhibition of Hsp90 appears to be detrimental as toxicities have been reported alongside induction of the pro-survival heat shock response. The development of Hsp90 isoform-selective inhibitors represents an alternative approach towards the treatment of cancer that may limit some of the detriments. Described herein is a structure-based approach to design isoform-selective inhibitors of Hsp90β, which induces the degradation of select Hsp90 clients without concomitant induction of Hsp90 levels. Together, these initial studies support the development of Hsp90β-selective inhibitors as a method to overcome the detriments associated with pan-inhibition.

PubMed: 29382832
DOI: 10.1038/s41467-017-02013-1

Experimental method

X-RAY DIFFRACTION (1.693 Å)