PDBsum entry 2exl

Chaperone

PDB id: 2exl

Contents

Protein chains

206 a.a. *

Ligands

GDM ×2

PG4 ×4

1PE

Waters ×282

* Residue conservation analysis

PDB id:

2exl

Name:

Chaperone

Title:

Grp94 n-terminal domain bound to geldanamycin

Structure:

Endoplasmin. Chain: a, b. Fragment: residues 69-337. Synonym: 94 kda glucose-regulated protein, grp94. Engineered: yes. Mutation: yes

Source:

Canis lupus familiaris. Dog. Organism_taxid: 9615. Strain: familiaris. Gene: tra1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.35Å R-factor: 0.221 R-free: 0.276

Authors:

P.N.Reardon,R.M.Immormino,D.T.Gewirth

Key ref:

R.M.Immormino et al. (2009). Different poses for ligand and chaperone in inhibitor-bound Hsp90 and GRP94: implications for paralog-specific drug design. J Mol Biol, 388, 1033-1042. PubMed id: 19361515

Date:

08-Nov-05 Release date: 24-Oct-06

Protein chains

P41148  (ENPL_CANLF) -  Endoplasmin from Canis lupus familiaris

Seq: 804 a.a.

Struc: 206 a.a.*

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

J Mol Biol 388:1033-1042 (2009)

PubMed id: 19361515

Different poses for ligand and chaperone in inhibitor-bound Hsp90 and GRP94: implications for paralog-specific drug design.

R.M.Immormino, L.E.Metzger, P.N.Reardon, D.E.Dollins, B.S.Blagg, D.T.Gewirth.

ABSTRACT

Hsp90 chaperones contain an N-terminal ATP binding site that has been effectively targeted by competitive inhibitors. Despite the myriad of inhibitors, none to date have been designed to bind specifically to just one of the four mammalian Hsp90 paralogs, which are cytoplasmic Hsp90alpha and beta, endoplasmic reticulum GRP94, and mitochondrial Trap-1. Given that each of the Hsp90 paralogs is responsible for chaperoning a distinct set of client proteins, specific targeting of one Hsp90 paralog may result in higher efficacy and therapeutic control. Specific inhibitors may also help elucidate the biochemical roles of each Hsp90 paralog. Here, we present side-by-side comparisons of the structures of yeast Hsp90 and mammalian GRP94, bound to the pan-Hsp90 inhibitors geldanamycin (Gdm) and radamide. These structures reveal paralog-specific differences in the Hsp90 and GRP94 conformations in response to Gdm binding. We also report significant variation in the pose and disparate binding affinities for the Gdm-radicicol chimera radamide when bound to the two paralogs, which may be exploited in the design of paralog-specific inhibitors.