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- PDB-3ldq: Crystal structure of HSC70/BAG1 in complex with small molecule in... -

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Basic information

Entry
Database: PDB / ID: 3ldq
TitleCrystal structure of HSC70/BAG1 in complex with small molecule inhibitor
Components
  • BAG family molecular chaperone regulator 1
  • Heat shock cognate 71 kDa protein
KeywordsCHAPERONE / GRP78 / HSP70 / HSC70 / HEAT SHOCK / PROTEIN FOLDING / ATP-BINDING / ADENOSINE / NUCLEOSIDE / NUCLEOTIDE-BINDING / STRESS RESPONSE / SMALL MOLECULE INHIBITOR / SELECTIVITY / Phosphoprotein / Apoptosis / Nucleus
Function / homology
Function and homology information


lumenal side of lysosomal membrane / regulation of protein import / negative regulation of supramolecular fiber organization / protein carrier chaperone / clathrin-sculpted gamma-aminobutyric acid transport vesicle membrane / Lipophagy / chaperone-mediated autophagy translocation complex disassembly / slow axonal transport / clathrin-uncoating ATPase activity / GABA synthesis, release, reuptake and degradation ...lumenal side of lysosomal membrane / regulation of protein import / negative regulation of supramolecular fiber organization / protein carrier chaperone / clathrin-sculpted gamma-aminobutyric acid transport vesicle membrane / Lipophagy / chaperone-mediated autophagy translocation complex disassembly / slow axonal transport / clathrin-uncoating ATPase activity / GABA synthesis, release, reuptake and degradation / protein targeting to lysosome involved in chaperone-mediated autophagy / adenyl-nucleotide exchange factor activity / late endosomal microautophagy / C3HC4-type RING finger domain binding / clathrin coat disassembly / negative regulation of NLRP3 inflammasome complex assembly / CHL1 interactions / ATP-dependent protein disaggregase activity / regulation of protein complex stability / membrane organization / Prp19 complex / presynaptic cytosol / protein folding chaperone complex / postsynaptic cytosol / Lysosome Vesicle Biogenesis / chaperone-mediated autophagy / cellular response to steroid hormone stimulus / Golgi Associated Vesicle Biogenesis / non-chaperonin molecular chaperone ATPase / chaperone cofactor-dependent protein refolding / regulation of protein-containing complex assembly / HSF1-dependent transactivation / response to unfolded protein / autophagosome / Regulation of HSF1-mediated heat shock response / Attenuation phase / Protein methylation / protein folding chaperone / ATP metabolic process / heat shock protein binding / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / cellular response to starvation / mRNA Splicing - Major Pathway / lysosomal lumen / G protein-coupled receptor binding / AUF1 (hnRNP D0) binds and destabilizes mRNA / ATP-dependent protein folding chaperone / spliceosomal complex / Late endosomal microautophagy / regulation of protein stability / PKR-mediated signaling / terminal bouton / mRNA splicing, via spliceosome / Chaperone Mediated Autophagy / melanosome / unfolded protein binding / protein-macromolecule adaptor activity / protein folding / Clathrin-mediated endocytosis / MHC class II protein complex binding / protein-folding chaperone binding / protein refolding / blood microparticle / Interleukin-4 and Interleukin-13 signaling / secretory granule lumen / ficolin-1-rich granule lumen / lysosome / protein stabilization / cell surface receptor signaling pathway / cadherin binding / ribonucleoprotein complex / lysosomal membrane / focal adhesion / negative regulation of DNA-templated transcription / dendrite / apoptotic process / ubiquitin protein ligase binding / Neutrophil degranulation / nucleolus / negative regulation of apoptotic process / enzyme binding / ATP hydrolysis activity / extracellular space / RNA binding / extracellular exosome / extracellular region / nucleoplasm / ATP binding / membrane / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
BAG domain / BAG domain superfamily / Molecular chaperone regulator BAG / BAG domain / BAG domain / BAG domain profile. / BAG domains, present in regulator of Hsp70 proteins / Defensin A-like - #30 / Defensin A-like / Heat shock hsp70 proteins family signature 2. ...BAG domain / BAG domain superfamily / Molecular chaperone regulator BAG / BAG domain / BAG domain / BAG domain profile. / BAG domains, present in regulator of Hsp70 proteins / Defensin A-like - #30 / Defensin A-like / Heat shock hsp70 proteins family signature 2. / Heat shock hsp70 proteins family signature 1. / Heat shock hsp70 proteins family signature 3. / Heat shock protein 70, conserved site / Heat shock protein 70kD, peptide-binding domain superfamily / Heat shock protein 70 family / Hsp70 protein / Heat shock protein 70kD, C-terminal domain superfamily / ATPase, substrate binding domain, subdomain 4 / Actin; Chain A, domain 4 / ATPase, nucleotide binding domain / Methane Monooxygenase Hydroxylase; Chain G, domain 1 / ATPase, nucleotide binding domain / Ubiquitin family / Ubiquitin homologues / Ubiquitin-like domain / Ubiquitin domain profile. / Nucleotidyltransferase; domain 5 / Ubiquitin-like domain superfamily / Alpha-Beta Complex / Up-down Bundle / 2-Layer Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
8-[(quinolin-2-ylmethyl)amino]adenosine / Heat shock cognate 71 kDa protein / BAG family molecular chaperone regulator 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsDokurno, P. / Surgenor, A.E. / Shaw, T. / Macias, A.T. / Massey, A.J. / Williamson, D.S.
CitationJournal: J.Med.Chem. / Year: 2011
Title: Adenosine-Derived Inhibitors of 78 kDa Glucose Regulated Protein (Grp78) ATPase: Insights into Isoform Selectivity.
Authors: Macias, A.T. / Williamson, D.S. / Allen, N. / Borgognoni, J. / Clay, A. / Daniels, Z. / Dokurno, P. / Drysdale, M.J. / Francis, G.L. / Graham, C.J. / Howes, R. / Matassova, N. / Murray, J.B. ...Authors: Macias, A.T. / Williamson, D.S. / Allen, N. / Borgognoni, J. / Clay, A. / Daniels, Z. / Dokurno, P. / Drysdale, M.J. / Francis, G.L. / Graham, C.J. / Howes, R. / Matassova, N. / Murray, J.B. / Parsons, R. / Shaw, T. / Surgenor, A.E. / Terry, L. / Wang, Y. / Wood, M. / Massey, A.J.
History
DepositionJan 13, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 26, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Heat shock cognate 71 kDa protein
B: BAG family molecular chaperone regulator 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,6673
Polymers55,2442
Non-polymers4231
Water6,017334
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1940 Å2
ΔGint1 kcal/mol
Surface area23090 Å2
MethodPISA
Unit cell
Length a, b, c (Å)40.774, 121.995, 54.250
Angle α, β, γ (deg.)90.00, 106.88, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Heat shock cognate 71 kDa protein / Heat shock 70 kDa protein 8


Mass: 42086.547 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSPA8, HSC70, HSP73, HSPA10 / Plasmid: PET101 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P11142
#2: Protein BAG family molecular chaperone regulator 1 / BAG-1 / Bcl-2-associated athanogene 1


Mass: 13157.168 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BAG1, HAP / Plasmid: PGEX-2T / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE3) / References: UniProt: Q99933
#3: Chemical ChemComp-3P1 / 8-[(quinolin-2-ylmethyl)amino]adenosine


Mass: 423.425 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H21N7O4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 334 / 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: 2.34 Å3/Da / Density % sol: 47.37 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 15% PEG3350, 0.1M TRIS BUFFER, 25MM SODIUM-POTASSIUM TARTRATE, pH 8.5, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.9724 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Nov 5, 2009 / Details: mirrors
RadiationMonochromator: mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9724 Å / Relative weight: 1
ReflectionResolution: 1.9→30 Å / Num. all: 39034 / Num. obs: 39034 / % possible obs: 97.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.5 % / Rmerge(I) obs: 0.055 / Net I/σ(I): 21
Reflection shellResolution: 1.9→1.97 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.193 / Mean I/σ(I) obs: 6 / Num. unique all: 3805 / % possible all: 95.4

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Processing

Software
NameVersionClassification
MxCuBEdata collection
MOLREPphasing
REFMAC5.2.0019refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 1HX1

1hx1


Resolution: 1.9→10 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.914 / SU B: 3.774 / SU ML: 0.113 / Cross valid method: THROUGHOUT / ESU R: 0.179 / ESU R Free: 0.167 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25597 1955 5 %RANDOM
Rwork0.20314 ---
obs0.2058 36900 98.08 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 29.84 Å2
Baniso -1Baniso -2Baniso -3
1--1.18 Å20 Å2-0.98 Å2
2---0.66 Å20 Å2
3---1.26 Å2
Refinement stepCycle: LAST / Resolution: 1.9→10 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3790 0 31 334 4155
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.0223878
X-RAY DIFFRACTIONr_angle_refined_deg1.4891.9595233
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4055486
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.21124.886176
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.06915712
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.8071526
X-RAY DIFFRACTIONr_chiral_restr0.1060.2603
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022874
X-RAY DIFFRACTIONr_nbd_refined0.2190.21830
X-RAY DIFFRACTIONr_nbtor_refined0.3010.22703
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1580.2317
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2370.255
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1980.223
X-RAY DIFFRACTIONr_mcbond_it1.0531.52503
X-RAY DIFFRACTIONr_mcangle_it1.65723901
X-RAY DIFFRACTIONr_scbond_it2.75931548
X-RAY DIFFRACTIONr_scangle_it4.3464.51332
LS refinement shellResolution: 1.9→1.948 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.315 129 -
Rwork0.249 2562 -
obs--93.7 %

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