Structure of the N-terminal domain of GRP94. Basis for ligand specificity and regulation

J Biol Chem. 2003 Nov 28;278(48):48330-8. doi: 10.1074/jbc.M308661200. Epub 2003 Sep 11.


GRP94, the endoplasmic reticulum (ER) paralog of the chaperone Hsp90, plays an essential role in the structural maturation or secretion of a subset of proteins destined for transport to the cell surface, such as the Toll-like receptors 2 and 4, and IgG, respectively. GRP94 differs from cytoplasmic Hsp90 by exhibiting very weak ATP binding and hydrolysis activity. GRP94 also binds selectively to a series of substituted adenosine analogs. The high resolution crystal structures at 1.75-2.1 A of the N-terminal and adjacent charged domains of GRP94 in complex with N-ethylcarboxamidoadenosine, radicicol, and 2-chlorodideoxyadenosine reveals a structural mechanism for ligand discrimination among hsp90 family members. The structures also identify a putative subdomain that may act as a ligand-responsive switch. The residues of the charged region fold into a disordered loop whose termini are ordered and continue the twisted beta sheet that forms the structural core of the N-domain. This continuation of the beta sheet past the charged domain suggests a structural basis for the association of the N-terminal and middle domains of the full-length chaperone.

MeSH terms

  • Adenosine / chemistry
  • Adenosine-5'-(N-ethylcarboxamide) / chemistry
  • Amino Acid Sequence
  • Animals
  • Crystallography, X-Ray
  • Cytoplasm / metabolism
  • Dideoxyadenosine / analogs & derivatives*
  • Dideoxyadenosine / chemistry
  • Dimerization
  • Dogs
  • Electrons
  • Endoplasmic Reticulum / metabolism
  • Glutathione Transferase / metabolism
  • HSP70 Heat-Shock Proteins / chemistry*
  • HSP90 Heat-Shock Proteins / chemistry
  • Lactones / chemistry
  • Ligands
  • Macrolides
  • Membrane Proteins / chemistry*
  • Models, Chemical
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • Recombinant Fusion Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Substrate Specificity


  • HSP70 Heat-Shock Proteins
  • HSP90 Heat-Shock Proteins
  • Lactones
  • Ligands
  • Macrolides
  • Membrane Proteins
  • Recombinant Fusion Proteins
  • glucose-regulated proteins
  • 2-chloro-2',3'-dideoxyadenosine
  • Adenosine-5'-(N-ethylcarboxamide)
  • Dideoxyadenosine
  • Glutathione Transferase
  • monorden
  • Adenosine

Associated data

  • PDB/1QY5
  • PDB/1QY8
  • PDB/1QYE
  • PDB/1QYH