PDBsum entry 3o2f

Chaperone/inhibitor

PDB id: 3o2f

Contents

Protein chains

228 a.a.

Ligands

P54 ×2

IPA ×4

GOL

Waters ×216

References listed in PDB file

Key reference

• Title: Paralog-Selective hsp90 inhibitors define tumor-Specific regulation of her2.
• Authors: P.D.Patel, P.Yan, P.M.Seidler, H.J.Patel, W.Sun, C.Yang, N.S.Que, T.Taldone, P.Finotti, R.A.Stephani, D.T.Gewirth, G.Chiosis.
• Ref.: Nat Chem Biol, 2013, 9, 677-684. [DOI no: 10.1038/nchembio.1335]
• PubMed id: 23995768

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.