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PDBsum entry 2o1v
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protein ligands metals Protein-protein interface(s) links
Chaperone PDB id
2o1v

 

 

 

 

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Contents
Protein chains
578 a.a. *
Ligands
ADP ×2
Metals
_MG ×4
Waters ×260
* Residue conservation analysis
PDB id:
2o1v
Name: Chaperone
Title: Structure of full length grp94 with adp bound
Structure: Endoplasmin. Chain: a, b. Fragment: residues 73-754. Synonym: heat shock protein 90 kda beta member 1, 94 kda glucose- regulated protein, grp94. Engineered: yes. Mutation: yes
Source: Canis lupus familiaris. Dog. Organism_taxid: 9615. Strain: familiaris. Gene: hsp90b1, tra1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Resolution:
2.45Å     R-factor:   0.250     R-free:   0.299
Authors: D.E.Dollins,J.J.Warren,R.M.Immormino,D.T.Gewirth
Key ref:
D.E.Dollins et al. (2007). Structures of GRP94-nucleotide complexes reveal mechanistic differences between the hsp90 chaperones. Mol Cell, 28, 41-56. PubMed id: 17936703 DOI: 10.1016/j.molcel.2007.08.024
Date:
29-Nov-06     Release date:   23-Oct-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P41148  (ENPL_CANLF) -  Endoplasmin from Canis lupus familiaris
Seq:
Struc: 		 
Seq:
Struc: 		804 a.a.
578 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 

 
DOI no: 10.1016/j.molcel.2007.08.024 Mol Cell 28:41-56 (2007)
PubMed id: 17936703  
 
 
Structures of GRP94-nucleotide complexes reveal mechanistic differences between the hsp90 chaperones.
D.E.Dollins, J.J.Warren, R.M.Immormino, D.T.Gewirth.
 
  ABSTRACT  
 
GRP94, an essential endoplasmic reticulum chaperone, is required for the conformational maturation of proteins destined for cell-surface display or export. The extent to which GRP94 and its cytosolic paralog, Hsp90, share a common mechanism remains controversial. GRP94 has not been shown conclusively to hydrolyze ATP or bind cochaperones, and both activities, by contrast, result in conformational changes and N-terminal dimerization in Hsp90 that are critical for its function. Here, we report the 2.4 A crystal structure of mammalian GRP94 in complex with AMPPNP and ADP. The chaperone is conformationally insensitive to the identity of the bound nucleotide, adopting a "twisted V" conformation that precludes N-terminal domain dimerization. We also present conclusive evidence that GRP94 possesses ATPase activity. Our observations provide a structural explanation for GRP94's observed rate of ATP hydrolysis and suggest a model for the role of ATP binding and hydrolysis in the GRP94 chaperone cycle.
 
  Selected figure(s)  
 
Figure 4.
Figure 4. The C-Terminal Domain of GRP94 Has Additional Dimer Interactions
(A and B) The C-terminal domain. Helices comprising the strap residues are shown in gold.
(C) A potential client-binding surface composed of Met-Met pairs and hydrophobic residues. 		Figure 5.
Figure 5. ADP- and AMPPNP-Bound GRP94 Have Identical Conformations
(A) Overlay of the two nucleotide-bound complexes. The AMPPNP complex is in blue, and the ADP complex is in cyan. Only one protomer of the GRP94 dimer is shown.
(B) Stereo view of the bound AMPPNP. SA omit electron density contoured at 1.3 σ is shown with a 2 Šcarve radius. The density for the nucleotide is shown in green, for the residues of the N domain in pink, and for the M domain in blue. The position of Arg448 is indicated, and the distance to the γ-phosphate of the AMPPNP is shown with a dashed line.
 
  The above figures are reprinted from an Open Access publication published by Cell Press: Mol Cell (2007, 28, 41-56) copyright 2007.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21183720 G.E.Karagöz, A.M.Duarte, H.Ippel, C.Uetrecht, T.Sinnige, M.van Rosmalen, J.Hausmann, A.J.Heck, R.Boelens, and S.G.Rüdiger (2011).
N-terminal domain of human Hsp90 triggers binding to the cochaperone p23.
  Proc Natl Acad Sci U S A, 108, 580-585.  
21335434 G.E.Karagöz, T.Sinnige, O.Hsieh, and S.G.Rüdiger (2011).
Expressed protein ligation for a large dimeric protein.
  Protein Eng Des Sel, 24, 495-501.  
21414251 K.A.Krukenberg, T.O.Street, L.A.Lavery, and D.A.Agard (2011).
Conformational dynamics of the molecular chaperone Hsp90.
  Q Rev Biophys, 44, 229-255.  
21474071 T.O.Street, L.A.Lavery, and D.A.Agard (2011).
Substrate binding drives large-scale conformational changes in the Hsp90 molecular chaperone.
  Mol Cell, 42, 96.  
  20865800 B.Liu, Y.Yang, Z.Qiu, M.Staron, F.Hong, Y.Li, S.Wu, Y.Li, B.Hao, R.Bona, D.Han, and Z.Li (2010).
Folding of Toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone.
  Nat Commun, 1, doi:10.1038/ncomms1070.  
20044986 J.C.Maynard, T.Pham, T.Zheng, A.Jockheck-Clark, H.B.Rankin, C.B.Newgard, E.P.Spana, and C.V.Nicchitta (2010).
Gp93, the Drosophila GRP94 ortholog, is required for gut epithelial homeostasis and nutrient assimilation-coupled growth control.
  Dev Biol, 339, 295-306.  
20352117 J.M.Han, N.H.Kwon, J.Y.Lee, S.J.Jeong, H.J.Jung, H.R.Kim, Z.Li, and S.Kim (2010).
Identification of gp96 as a novel target for treatment of autoimmune disease in mice.
  PLoS One, 5, e9792.  
20651736 J.Trepel, M.Mollapour, G.Giaccone, and L.Neckers (2010).
Targeting the dynamic HSP90 complex in cancer.
  Nat Rev Cancer, 10, 537-549.  
20001734 M.Csala, E.Margittai, and G.Bánhegyi (2010).
Redox control of endoplasmic reticulum function.
  Antioxid Redox Signal, 13, 77.  
20531426 M.Taipale, D.F.Jarosz, and S.Lindquist (2010).
HSP90 at the hub of protein homeostasis: emerging mechanistic insights.
  Nat Rev Mol Cell Biol, 11, 515-528.  
20670895 M.Zhang, Y.Kadota, C.Prodromou, K.Shirasu, and L.H.Pearl (2010).
Structural basis for assembly of Hsp90-Sgt1-CHORD protein complexes: implications for chaperoning of NLR innate immunity receptors.
  Mol Cell, 39, 269-281.
PDB code: 2xcm
  20971738 R.Ye, O.A.Mareninova, E.Barron, M.Wang, D.R.Hinton, S.J.Pandol, and A.S.Lee (2010).
Grp78 heterozygosity regulates chaperone balance in exocrine pancreas with differential response to cerulein-induced acute pancreatitis.
  Am J Pathol, 177, 2827-2836.  
20977755 S.Z.Usmani, R.D.Bona, G.Chiosis, and Z.Li (2010).
The anti-myeloma activity of a novel purine scaffold HSP90 inhibitor PU-H71 is via inhibition of both HSP90A and HSP90B1.
  J Hematol Oncol, 3, 40.  
  19890989 T.O.Street, K.A.Krukenberg, J.Rosgen, D.W.Bolen, and D.A.Agard (2010).
Osmolyte-induced conformational changes in the Hsp90 molecular chaperone.
  Protein Sci, 19, 57-65.  
19752220 A.Lev, P.Dimberu, S.R.Das, J.C.Maynard, C.V.Nicchitta, J.R.Bennink, and J.W.Yewdell (2009).
Efficient cross-priming of antiviral CD8+ T cells by antigen donor cells is GRP94 independent.
  J Immunol, 183, 4205-4210.  
19032597 C.K.Vaughan, P.W.Piper, L.H.Pearl, and C.Prodromou (2009).
A common conformationally coupled ATPase mechanism for yeast and human cytoplasmic HSP90s.
  FEBS J, 276, 199-209.  
19786553 C.Morales, S.Wu, Y.Yang, B.Hao, and Z.Li (2009).
Drosophila glycoprotein 93 Is an ortholog of mammalian heat shock protein gp96 (grp94, HSP90b1, HSPC4) and retains disulfide bond-independent chaperone function for TLRs and integrins.
  J Immunol, 183, 5121-5128.  
19300478 G.Morra, G.Verkhivker, and G.Colombo (2009).
Modeling signal propagation mechanisms and ligand-based conformational dynamics of the Hsp90 molecular chaperone full-length dimer.
  PLoS Comput Biol, 5, e1000323.  
19554567 K.A.Krukenberg, U.M.Böttcher, D.R.Southworth, and D.A.Agard (2009).
Grp94, the endoplasmic reticulum Hsp90, has a similar solution conformation to cytosolic Hsp90 in the absence of nucleotide.
  Protein Sci, 18, 1815-1827.  
19234467 M.Hessling, K.Richter, and J.Buchner (2009).
Dissection of the ATP-induced conformational cycle of the molecular chaperone Hsp90.
  Nat Struct Mol Biol, 16, 287-293.  
19696785 M.Retzlaff, M.Stahl, H.C.Eberl, S.Lagleder, J.Beck, H.Kessler, and J.Buchner (2009).
Hsp90 is regulated by a switch point in the C-terminal domain.
  EMBO Rep, 10, 1147-1153.  
19685544 M.Sgobba, and G.Rastelli (2009).
Structure-based and in silico design of Hsp90 inhibitors.
  ChemMedChem, 4, 1399-1409.  
19553666 O.Hainzl, M.C.Lapina, J.Buchner, and K.Richter (2009).
The charged linker region is an important regulator of Hsp90 function.
  J Biol Chem, 284, 22559-22567.  
19553200 O.Ostrovsky, C.A.Makarewich, E.L.Snapp, and Y.Argon (2009).
An essential role for ATP binding and hydrolysis in the chaperone activity of GRP94 in cells.
  Proc Natl Acad Sci U S A, 106, 11600-11605.  
19361515 R.M.Immormino, L.E.Metzger, P.N.Reardon, D.E.Dollins, B.S.Blagg, and D.T.Gewirth (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.
PDB codes: 2exl 2fxs 2gfd
19179103 Y.Li, T.Zhang, S.J.Schwartz, and D.Sun (2009).
New developments in Hsp90 inhibitors as anti-cancer therapeutics: mechanisms, clinical perspective and more potential.
  Drug Resist Updat, 12, 17-27.  
18287101 A.Leskovar, H.Wegele, N.D.Werbeck, J.Buchner, and J.Reinstein (2008).
The ATPase cycle of the mitochondrial Hsp90 analog Trap1.
  J Biol Chem, 283, 11677-11688.  
19061638 D.R.Southworth, and D.A.Agard (2008).
Species-dependent ensembles of conserved conformational states define the Hsp90 chaperone ATPase cycle.
  Mol Cell, 32, 631-640.  
18643792 G.Bánhegyi, J.Mandl, and M.Csala (2008).
Redox-based endoplasmic reticulum dysfunction in neurological diseases.
  J Neurochem, 107, 20-34.  
18242075 H.R.Saibil (2008).
Chaperone machines in action.
  Curr Opin Struct Biol, 18, 35-42.  
18462680 K.A.Krukenberg, F.Förster, L.M.Rice, A.Sali, and D.A.Agard (2008).
Multiple conformations of E. coli Hsp90 in solution: insights into the conformational dynamics of Hsp90.
  Structure, 16, 755-765.  
18400751 K.Richter, J.Soroka, L.Skalniak, A.Leskovar, M.Hessling, J.Reinstein, and J.Buchner (2008).
Conserved conformational changes in the ATPase cycle of human Hsp90.
  J Biol Chem, 283, 17757-17765.  
18462669 S.E.Jackson (2008).
The solution to multiple structures.
  Structure, 16, 659-661.  
18442971 S.K.Wandinger, K.Richter, and J.Buchner (2008).
The Hsp90 chaperone machinery.
  J Biol Chem, 283, 18473-18477.  
19003179 S.U.Khan, and M.Schröder (2008).
Engineering of chaperone systems and of the unfolded protein response.
  Cytotechnology, 57, 207-231.  
18693757 V.V.Ivanenkov, J.Sévigny, and T.L.Kirley (2008).
Trafficking and intracellular ATPase activity of human ecto-nucleotidase NTPDase3 and the effect of ER-targeted NTPDase3 on protein folding.
  Biochemistry, 47, 9184-9197.  
17964255 K.Richter, J.Reinstein, and J.Buchner (2007).
A Grp on the Hsp90 mechanism.
  Mol Cell, 28, 177-179.  
18022558 L.Neckers, A.Kern, and S.Tsutsumi (2007).
Hsp90 inhibitors disrupt mitochondrial homeostasis in cancer cells.
  Chem Biol, 14, 1204-1206.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.

 

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