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- PDB-5ttz: Crystal structure of Grp94 bound to isoform-selective inhibitor m... -

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Basic information

Entry
Database: PDB / ID: 5ttz
TitleCrystal structure of Grp94 bound to isoform-selective inhibitor methyl 2-(2-(1-(4-bromobenzyl)-1H-imidazol-2-yl)ethyl)-3-chloro-4,6-dihydroxybenzoate
ComponentsEndoplasmin
KeywordsCHAPERONE / INHIBITOR / BnIm Scaffold / ATP Binding Site / CHAPERONE - INHIBITOR complex
Function / homology
Function and homology information


Trafficking and processing of endosomal TLR / Scavenging by Class A Receptors / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / Interleukin-4 and Interleukin-13 signaling / Post-translational protein phosphorylation / sarcoplasmic reticulum lumen / ERAD pathway / ATP-dependent protein folding chaperone / unfolded protein binding / melanosome ...Trafficking and processing of endosomal TLR / Scavenging by Class A Receptors / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / Interleukin-4 and Interleukin-13 signaling / Post-translational protein phosphorylation / sarcoplasmic reticulum lumen / ERAD pathway / ATP-dependent protein folding chaperone / unfolded protein binding / melanosome / protein folding / response to heat / DNA damage response / perinuclear region of cytoplasm / endoplasmic reticulum / ATP hydrolysis activity / ATP binding / cytosol
Similarity search - Function
Endoplasmic reticulum targeting sequence. / Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / HSP90, C-terminal domain / Heat shock protein Hsp90, N-terminal / Heat shock protein Hsp90 family / Hsp90 protein / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-like ATPase, C-terminal domain / Heat Shock Protein 90 ...Endoplasmic reticulum targeting sequence. / Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / HSP90, C-terminal domain / Heat shock protein Hsp90, N-terminal / Heat shock protein Hsp90 family / Hsp90 protein / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-like ATPase, C-terminal domain / Heat Shock Protein 90 / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase / Histidine kinase/HSP90-like ATPase superfamily / Ribosomal protein S5 domain 2-type fold / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-7KY / DI(HYDROXYETHYL)ETHER / TRIETHYLENE GLYCOL / Endoplasmin
Similarity search - Component
Biological speciesCanis lupus familiaris (dog)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.707 Å
AuthorsLieberman, R.L. / Huard, D.J.E.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Eye Institute (NIH/NEI)R01EY021205 United States
CitationJournal: Sci Rep / Year: 2017
Title: Isoform-selective Hsp90 inhibition rescues model of hereditary open-angle glaucoma.
Authors: Stothert, A.R. / Suntharalingam, A. / Tang, X. / Crowley, V.M. / Mishra, S.J. / Webster, J.M. / Nordhues, B.A. / Huard, D.J.E. / Passaglia, C.L. / Lieberman, R.L. / Blagg, B.S.J. / Blair, L. ...Authors: Stothert, A.R. / Suntharalingam, A. / Tang, X. / Crowley, V.M. / Mishra, S.J. / Webster, J.M. / Nordhues, B.A. / Huard, D.J.E. / Passaglia, C.L. / Lieberman, R.L. / Blagg, B.S.J. / Blair, L.J. / Koren, J. / Dickey, C.A.
History
DepositionNov 4, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 10, 2018Provider: repository / Type: Initial release
Revision 1.1Dec 11, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Oct 4, 2023Group: Advisory / Data collection ...Advisory / Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_unobs_or_zero_occ_atoms
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Endoplasmin
B: Endoplasmin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,1128
Polymers52,3752
Non-polymers1,7366
Water66737
1
A: Endoplasmin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,7593
Polymers26,1881
Non-polymers5722
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Endoplasmin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,3525
Polymers26,1881
Non-polymers1,1654
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)65.237, 84.420, 95.473
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Endoplasmin / 94 kDa glucose-regulated protein / GRP-94 / Heat shock protein 90 kDa beta member 1


Mass: 26187.615 Da / Num. of mol.: 2 / Fragment: residues 69-337
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Canis lupus familiaris (dog) / Gene: HSP90B1, GRP94, TRA1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P41148

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Non-polymers , 6 types, 43 molecules

#2: Chemical ChemComp-7KY / methyl 2-(2-{1-[(4-bromophenyl)methyl]-1H-imidazol-2-yl}ethyl)-3-chloro-4,6-dihydroxybenzoate


Mass: 465.725 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H18BrClN2O4
#3: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#4: Chemical ChemComp-PG4 / TETRAETHYLENE GLYCOL


Mass: 194.226 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18O5 / Comment: precipitant*YM
#5: Chemical ChemComp-PGE / TRIETHYLENE GLYCOL


Mass: 150.173 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14O4
#6: Chemical ChemComp-PE4 / 2-{2-[2-(2-{2-[2-(2-ETHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHOXY]-ETHOXY}-ETHANOL / POLYETHYLENE GLYCOL PEG4000


Mass: 354.436 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H34O8 / Comment: precipitant*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 37 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.51 Å3/Da / Density % sol: 50.99 %
Crystal growTemperature: 289.15 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: Protein at 30 mg/mL in 0.1 M Tris pH 7.5 was mixed 1:1 with mother liquor comprised of 35% PEG400, 0.1 M Tris pH 7.5, and 80 mM MgCl2. Crystals were harvested and soaked in mother liquor ...Details: Protein at 30 mg/mL in 0.1 M Tris pH 7.5 was mixed 1:1 with mother liquor comprised of 35% PEG400, 0.1 M Tris pH 7.5, and 80 mM MgCl2. Crystals were harvested and soaked in mother liquor containing 20 mM inhibitor. A layer of glycerol was then added through which crystals were harvested and cryo-cooled in liquid nitrogen.

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Data collection

DiffractionMean temperature: 80 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Jun 25, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.707→47.74 Å / Num. obs: 217928 / % possible obs: 97.71 % / Redundancy: 14.6 % / Rmerge(I) obs: 0.121 / Net I/σ(I): 22.11
Reflection shellRmerge(I) obs: 0.663

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2GFD

2gfd


Resolution: 2.707→47.736 Å / SU ML: 0.42 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 31.51
RfactorNum. reflection% reflection
Rfree0.2855 1453 10 %
Rwork0.1992 --
obs0.2076 14528 97.4 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.707→47.736 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3307 0 110 37 3454
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.013462
X-RAY DIFFRACTIONf_angle_d1.2724648
X-RAY DIFFRACTIONf_dihedral_angle_d15.5881260
X-RAY DIFFRACTIONf_chiral_restr0.049525
X-RAY DIFFRACTIONf_plane_restr0.005580
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.7069-2.80370.37171210.26931101X-RAY DIFFRACTION83
2.8037-2.91590.37771370.26241227X-RAY DIFFRACTION94
2.9159-3.04860.32711450.23331301X-RAY DIFFRACTION98
3.0486-3.20930.32061450.21671307X-RAY DIFFRACTION100
3.2093-3.41030.29581480.18591336X-RAY DIFFRACTION100
3.4103-3.67350.25281490.191337X-RAY DIFFRACTION100
3.6735-4.0430.28871470.17921323X-RAY DIFFRACTION100
4.043-4.62760.27161500.15991353X-RAY DIFFRACTION100
4.6276-5.82870.25821510.18751356X-RAY DIFFRACTION100
5.8287-47.74390.25961600.22241434X-RAY DIFFRACTION99
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
12.88410.89451.53872.17950.58773.83170.14820.0202-0.02350.0922-0.15020.0130.1951-0.12410.03360.21450.04930.06160.2937-0.03610.3515-121.7322120.510941.0608
22.04880.21851.08883.7311-0.40212.86250.16650.0776-0.2042-0.0935-0.0752-0.11920.35920.3793-0.07260.2278-0.00590.00950.3559-0.07260.3903-124.2626116.599441.5478
33.39270.49791.41781.8464-0.22462.9970.10770.17420.0077-0.04260.0180.02190.1290.0767-0.15680.25420.07110.05710.3053-0.0260.3584-121.2098160.973944.0482
42.9803-0.20571.2973.1975-0.69642.88830.01590.0926-0.0438-0.2396-0.0522-0.17310.23810.25780.05260.22280.03080.01990.329-0.06410.3308-124.0572159.240944.939
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain A and resid 74:160)
2X-RAY DIFFRACTION2(chain A and resid 161:337)
3X-RAY DIFFRACTION3(chain B and resid 74:144)
4X-RAY DIFFRACTION4(chain B and resid 145:337)

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