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- PDB-6asp: Structure of Grp94 with methyl 3-chloro-2-(2-(1-(2-ethoxybenzyl)-... -

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Basic information

Entry
Database: PDB / ID: 6asp
TitleStructure of Grp94 with methyl 3-chloro-2-(2-(1-(2-ethoxybenzyl)-1 H-imidazol-2-yl)ethyl)-4,6-dihydroxybenzoate, a Grp94-selective inhibitor and promising therapeutic lead for treating myocilin-associated glaucoma
ComponentsEndoplasmin
KeywordsCHAPERONE/INHIBITOR / Grp94 / Hsp90 / Inhibitor / Glaucoma / 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 / perinuclear region of cytoplasm / endoplasmic reticulum / ATP hydrolysis activity / ATP binding
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-V2C / Endoplasmin
Similarity search - Component
Biological speciesCanis lupus familiaris (dog)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.696 Å
AuthorsHuard, D.J.E. / Lieberman, R.L.
CitationJournal: ACS Chem. Biol. / Year: 2018
Title: Trifunctional High-Throughput Screen Identifies Promising Scaffold To Inhibit Grp94 and Treat Myocilin-Associated Glaucoma.
Authors: Huard, D.J.E. / Crowley, V.M. / Du, Y. / Cordova, R.A. / Sun, Z. / Tomlin, M.O. / Dickey, C.A. / Koren, J. / Blair, L. / Fu, H. / Blagg, B.S.J. / Lieberman, R.L.
History
DepositionAug 25, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 18, 2018Provider: repository / Type: Initial release
Revision 1.1May 2, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Apr 17, 2019Group: Author supporting evidence / Data collection / Category: pdbx_audit_support
Revision 1.3Oct 4, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _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)58,97023
Polymers52,3752
Non-polymers6,59421
Water66737
1
A: Endoplasmin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,95416
Polymers26,1881
Non-polymers4,76615
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Endoplasmin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,0167
Polymers26,1881
Non-polymers1,8296
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.661, 84.772, 96.013
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#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: UNP residues 69-286, GGGG linker, 328-337
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) / References: UniProt: P41148
#2: Chemical
ChemComp-P33 / 3,6,9,12,15,18-HEXAOXAICOSANE-1,20-DIOL / HEPTAETHYLENE GLYCOL / PEG330


Mass: 326.383 Da / Num. of mol.: 17 / Source method: obtained synthetically / Formula: C14H30O8 / Comment: precipitant*YM
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-V2C / methyl 3-chloro-2-(2-(1-(2-ethoxybenzyl)-1 H-imidazol-2-yl)ethyl)-4,6-dihydroxybenzoate


Mass: 430.881 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H23ClN2O5
#5: 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: 2.55 Å3/Da / Density % sol: 51.78 %
Crystal growTemperature: 289.2 K / Method: vapor diffusion, sitting drop / pH: 7.8
Details: 1:1 30 mg/mL protein in 100 mM bicine, pH 7.8 against mother liquor (37% PEG400, 5% glycerol, 100 mM bicine, pH 7.8, 75 mM magnesium chloride). Crystals were harvested, and soaked for 48 ...Details: 1:1 30 mg/mL protein in 100 mM bicine, pH 7.8 against mother liquor (37% PEG400, 5% glycerol, 100 mM bicine, pH 7.8, 75 mM magnesium chloride). Crystals were harvested, and soaked for 48 hours in mother liquor containing 3.69 mM inhibitor. After soaking, glycerol was added to ~25% final concentration.

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Data collection

DiffractionMean temperature: 197.5 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Nov 22, 2016
RadiationMonochromator: double crystal Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.696→38.78 Å / Num. obs: 15293 / % possible obs: 99 % / Redundancy: 13.8 % / Biso Wilson estimate: 41.77 Å2 / Rmerge(I) obs: 0.1301 / Net I/σ(I): 22.46
Reflection shellResolution: 2.696→2.792 Å / Rmerge(I) obs: 0.6753

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 2GFD

2gfd


Resolution: 2.696→38.776 Å / SU ML: 0.29 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 25.31 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2377 1527 10 %
Rwork0.1777 --
obs0.1836 15264 99.41 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.696→38.776 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3378 0 164 37 3579
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.013576
X-RAY DIFFRACTIONf_angle_d1.2444787
X-RAY DIFFRACTIONf_dihedral_angle_d18.2562102
X-RAY DIFFRACTIONf_chiral_restr0.068552
X-RAY DIFFRACTIONf_plane_restr0.007587
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.6955-2.78250.28221330.21441191X-RAY DIFFRACTION96
2.7825-2.88190.31071330.21711213X-RAY DIFFRACTION100
2.8819-2.99720.26611380.19711242X-RAY DIFFRACTION100
2.9972-3.13360.26161380.18441242X-RAY DIFFRACTION100
3.1336-3.29870.25041360.17941223X-RAY DIFFRACTION100
3.2987-3.50530.25361370.16851237X-RAY DIFFRACTION100
3.5053-3.77570.21191390.16021245X-RAY DIFFRACTION100
3.7757-4.15530.21081400.1551261X-RAY DIFFRACTION100
4.1553-4.75560.20761400.14091258X-RAY DIFFRACTION100
4.7556-5.98810.23831440.19111289X-RAY DIFFRACTION100
5.9881-38.77960.23481490.20821336X-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)
10.55460.27690.03180.1044-0.03170.2766-0.52290.7792-0.41310.23910.7923-0.3383-0.08440.19040.02840.31790.165-0.01870.25710.02870.1801-60.157332.9049-69.5076
20.39920.17610.23330.3174-0.26710.7160.0331-0.01050.04740.0398-0.08530.08660.11890.0082-0.00010.1838-0.00240.02580.1873-0.04540.218-55.946837.3784-49.9715
30.2817-0.02970.09030.16450.03960.1159-0.26680.15390.0138-0.4162-0.5505-0.30740.17830.8112-0.050.49650.25230.12550.9209-0.05450.4585-48.621931.0111-69.551
41.27860.0364-0.08190.75720.42711.19530.2165-0.0888-0.1792-0.0007-0.1692-0.1050.15420.02070.00040.2179-0.0249-0.05960.1606-0.03810.2292-61.909531.9464-50.3675
50.19890.16510.03710.092-0.0830.4892-0.3110.22090.50690.21710.40740.04080.1770.29550.00940.34710.0966-0.01880.3291-0.02250.1147-59.998974.8129-66.2663
60.4308-0.20180.30140.3287-0.2840.35190.0985-0.14360.01210.0609-0.0497-0.053-0.0295-0.11460.00010.1686-0.00580.01270.2131-0.04590.1486-55.398177.1121-44.5132
72.1098-0.31940.48910.92440.46351.9537-0.0179-0.00240.0332-0.05390.0454-0.06260.02020.09570.00110.1201-0.0053-0.00330.138-0.04990.1428-59.302274.97-50.9923
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 74 through 96 )
2X-RAY DIFFRACTION2chain 'A' and (resid 97 through 164 )
3X-RAY DIFFRACTION3chain 'A' and (resid 165 through 195 )
4X-RAY DIFFRACTION4chain 'A' and (resid 196 through 337 )
5X-RAY DIFFRACTION5chain 'B' and (resid 74 through 96 )
6X-RAY DIFFRACTION6chain 'B' and (resid 97 through 149 )
7X-RAY DIFFRACTION7chain 'B' and (resid 150 through 337 )

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