3O0I

Structure of the human Hsp90-alpha N-domain bound to the hsp90 inhibitor PU-H54

Summary for 3O0I

• Entry DOI: 10.2210/pdb3o0i/pdb
• Related: 3C11
• Descriptor: HSP90AA1 protein, 8-[(2,4-dimethylphenyl)sulfanyl]-3-pent-4-yn-1-yl-3H-purin-6-amine (3 entities in total)
• Functional Keywords: hsp90 heat-shock proteins, chaperone-inhibitor complex, chaperone/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 29110.59

Authors

Seidler, P.M.,Gewirth, D.T. (deposition date: 2010-07-19, release date: 2011-10-05, Last modification date: 2024-02-21)

Primary citation

Patel, P.D.,Yan, P.,Seidler, P.M.,Patel, H.J.,Sun, W.,Yang, C.,Que, N.S.,Taldone, T.,Finotti, P.,Stephani, R.A.,Gewirth, D.T.,Chiosis, G.
Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2.
Nat.Chem.Biol., 9:677-684, 2013

PubMed Abstract: Although the Hsp90 chaperone family, comprised in humans of four paralogs, Hsp90α, Hsp90β, Grp94 and Trap-1, has important roles in malignancy, the contribution of each paralog to the cancer phenotype is poorly understood. This is in large part because reagents to study paralog-specific functions in cancer cells have been unavailable. Here we combine compound library screening with structural and computational analyses to identify purine-based chemical tools that are specific for Hsp90 paralogs. We show that Grp94 selectivity is due to the insertion of these compounds into a new allosteric pocket. We use these tools to demonstrate that cancer cells use individual Hsp90 paralogs to regulate a client protein in a tumor-specific manner and in response to proteome alterations. Finally, we provide new mechanistic evidence explaining why selective Grp94 inhibition is particularly efficacious in certain breast cancers.

PubMed: 23995768
DOI: 10.1038/nchembio.1335

Experimental method

X-RAY DIFFRACTION (1.47 Å)