PDBsum entry 3o2f

Chaperone/inhibitor

PDB id: 3o2f

Contents

Protein chains

228 a.a.

Ligands

P54 ×2

IPA ×4

GOL

Waters ×216

PDB id:

3o2f

Name:

Chaperone/inhibitor

Title:

Structure of the n-domain of grp94 bound to the hsp90 inhibitor pu-h54

Structure:

Endoplasmin. Chain: a, b. Fragment: unp residues 69-286, 328-337. Synonym: heat shock protein 90 kda beta member 1, 94 kda glucose- regulated protein, grp-94. Engineered: yes

Source:

Canis lupus familiaris. Dogs. Organism_taxid: 9615. Gene: grp94, hsp90b1, tra1. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.00Å R-factor: 0.236 R-free: 0.269

Authors:

P.M.Seidler,D.T.Gewirth

Key ref:

P.D.Patel et al. (2013). Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2. Nat Chem Biol, 9, 677-684. PubMed id: 23995768 DOI: 10.1038/nchembio.1335

Date:

22-Jul-10 Release date: 05-Oct-11

Protein chains

P41148  (ENPL_CANLF) -  Endoplasmin from Canis lupus familiaris

Seq: 804 a.a.

Struc: 228 a.a.*

* PDB and UniProt seqs differ at 8 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1038/nchembio.1335

Nat Chem Biol 9:677-684 (2013)

PubMed id: 23995768

Paralog-selective Hsp90 inhibitors define tumor-specific regulation of HER2.

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.

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.