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- PDB-6asq: Structure of Grp94 bound to methyl 2-[2-(2-benzylpyridin-3-yl)eth... -

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Basic information

Entry
Database: PDB / ID: 6asq
TitleStructure of Grp94 bound to methyl 2-[2-(2-benzylpyridin-3-yl)ethyl]-3-chloro-4,6-dihydroxybenzoate, a pan-Hsp90 inhibitor
ComponentsEndoplasmin
KeywordsCHAPERONE/INHIBITOR / Grp94 / Hsp90 / Inhibitor / 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
3,6,9,12,15,18,21-HEPTAOXATRICOSANE-1,23-DIOL / DI(HYDROXYETHYL)ETHER / Chem-VC4 / Endoplasmin
Similarity search - Component
Biological speciesCanis lupus familiaris (dog)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.35 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 / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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)58,67324
Polymers52,3752
Non-polymers6,29822
Water1,40578
1
A: Endoplasmin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,57513
Polymers26,1881
Non-polymers3,38712
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Endoplasmin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,09811
Polymers26,1881
Non-polymers2,91110
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.431, 84.717, 95.759
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: 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

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Non-polymers , 5 types, 100 molecules

#2: Chemical
ChemComp-PE8 / 3,6,9,12,15,18,21-HEPTAOXATRICOSANE-1,23-DIOL


Mass: 370.436 Da / Num. of mol.: 13 / Source method: obtained synthetically / Formula: C16H34O9
#3: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C4H10O3
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-VC4 / methyl 2-[2-(2-benzylpyridin-3-yl)ethyl]-3-chloro-4,6-dihydroxybenzoate


Mass: 397.852 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H20ClNO4 / Feature type: SUBJECT OF INVESTIGATION
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 78 / 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: 2.53 Å3/Da / Density % sol: 51.45 %
Crystal growTemperature: 289.2 K / Method: vapor diffusion, hanging 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 2.5 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: Oct 21, 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: 2.35→42.36 Å / Num. obs: 22770 / % possible obs: 100 % / Redundancy: 14.3 % / Rmerge(I) obs: 0.09377 / Net I/σ(I): 24.75
Reflection shellResolution: 2.35→2.434 Å / Rmerge(I) obs: 0.4773

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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: 2.35→42.359 Å / SU ML: 0.25 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 25.94
RfactorNum. reflection% reflection
Rfree0.2367 1997 8.78 %
Rwork0.1966 --
obs0.2001 22739 99.75 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.35→42.359 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3441 0 218 78 3737
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0043692
X-RAY DIFFRACTIONf_angle_d0.84914
X-RAY DIFFRACTIONf_dihedral_angle_d17.2782185
X-RAY DIFFRACTIONf_chiral_restr0.044554
X-RAY DIFFRACTIONf_plane_restr0.003595
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3502-2.4090.29321380.22021435X-RAY DIFFRACTION98
2.409-2.47410.2951410.2211457X-RAY DIFFRACTION100
2.4741-2.54690.27591400.21111451X-RAY DIFFRACTION100
2.5469-2.62910.23991400.21061464X-RAY DIFFRACTION100
2.6291-2.72310.25721420.22241469X-RAY DIFFRACTION100
2.7231-2.83210.30361410.22931468X-RAY DIFFRACTION100
2.8321-2.96090.25211400.21271457X-RAY DIFFRACTION100
2.9609-3.1170.24171430.21921486X-RAY DIFFRACTION100
3.117-3.31220.22951420.20491469X-RAY DIFFRACTION100
3.3122-3.56780.21811420.19441478X-RAY DIFFRACTION100
3.5678-3.92660.20421430.17661483X-RAY DIFFRACTION100
3.9266-4.49430.22281440.15951511X-RAY DIFFRACTION100
4.4943-5.66020.20671460.18081515X-RAY DIFFRACTION100
5.6602-42.36540.24621550.20711599X-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)
12.07530.12170.76211.272-0.18951.69380.07280.02590.0352-0.093-0.08580.05780.12660.0485-0.010.1894-0.00370.03140.1917-0.05170.2071-56.8504120.7859-55.0347
20.25630.2690.11530.35910.03130.13840.45650.80950.2766-0.9822-0.5517-0.32910.49320.27630.24830.67580.17980.07491.4056-0.14190.8589-48.3189119.556-72.3821
32.1769-0.49150.63772.35370.07891.4520.0673-0.0974-0.17770.0108-0.05630.04040.1912-0.0159-0.02260.2114-0.02650.01310.1939-0.04730.2363-60.5406116.1209-51.2809
41.9592-0.73820.52173.5932-0.85822.0254-0.07920.2062-0.0099-0.18730.0691-0.47990.3890.2064-0.01090.37970.01270.02750.33020.01510.1994-59.7802159.5762-66.0886
53.28911.44870.44782.2665-0.11281.22460.0672-0.2360.15670.1646-0.01540.02550.0238-0.0126-0.03120.17510.0275-0.0050.218-0.03610.1572-55.2425161.5938-44.4542
60.8805-0.14330.64063.41840.25811.4666-0.02060.65770.0665-0.64660.014-0.7482-0.15530.78510.1480.307-0.02740.05790.6017-0.0370.4227-51.2796163.68-61.6908
72.4819-0.34660.50351.82460.19111.92910.0347-0.1266-0.0409-0.0195-0.0654-0.00470.1529-0.04470.02420.1704-0.0252-0.00490.1882-0.04520.1709-61.7031158.0676-46.9328
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 74 through 164 )
2X-RAY DIFFRACTION2chain 'A' and (resid 165 through 179 )
3X-RAY DIFFRACTION3chain 'A' and (resid 180 through 337 )
4X-RAY DIFFRACTION4chain 'B' and (resid 74 through 96 )
5X-RAY DIFFRACTION5chain 'B' and (resid 97 through 149 )
6X-RAY DIFFRACTION6chain 'B' and (resid 150 through 197 )
7X-RAY DIFFRACTION7chain 'B' and (resid 198 through 337 )

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