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Basic information

Entry
Database: PDB / ID: 5aqs
TitleFragment-based screening of HSP70 sheds light on the functional role of ATP-binding site residues
Components
  • BAG FAMILY MOLECULAR CHAPERONE REGULATOR 1
  • HEAT SHOCK COGNATE 71 KDA PROTEIN
KeywordsCHAPERONE / HEAT SHOCK PROTEIN / HSP70 / HSP72 / HSC70 / ATPASE / BAG1 / FRAGMENT
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
ISOQUINOLIN-1-AMINE / Heat shock cognate 71 kDa protein / BAG family molecular chaperone regulator 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsJones, A.M. / Westwood, I.M. / Osborne, J.D. / Matthews, T.P. / Cheeseman, M.D. / Rowlands, M.G. / Jeganathan, F. / Burke, R. / Lee, D. / Kadi, N. ...Jones, A.M. / Westwood, I.M. / Osborne, J.D. / Matthews, T.P. / Cheeseman, M.D. / Rowlands, M.G. / Jeganathan, F. / Burke, R. / Lee, D. / Kadi, N. / Liu, M. / Richards, M. / McAndrew, C. / Yahya, N. / Dobson, S.E. / Jones, K. / Workman, P. / Collins, I. / van Montfort, R.L.M.
CitationJournal: Sci Rep / Year: 2016
Title: A fragment-based approach applied to a highly flexible target: Insights and challenges towards the inhibition of HSP70 isoforms.
Authors: Jones, A.M. / Westwood, I.M. / Osborne, J.D. / Matthews, T.P. / Cheeseman, M.D. / Rowlands, M.G. / Jeganathan, F. / Burke, R. / Lee, D. / Kadi, N. / Liu, M. / Richards, M. / McAndrew, C. / ...Authors: Jones, A.M. / Westwood, I.M. / Osborne, J.D. / Matthews, T.P. / Cheeseman, M.D. / Rowlands, M.G. / Jeganathan, F. / Burke, R. / Lee, D. / Kadi, N. / Liu, M. / Richards, M. / McAndrew, C. / Yahya, N. / Dobson, S.E. / Jones, K. / Workman, P. / Collins, I. / van Montfort, R.L.
History
DepositionSep 22, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 5, 2016Provider: repository / Type: Initial release
Revision 1.1Jul 5, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.2Sep 13, 2017Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.name
Revision 1.3Jan 10, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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
C: HEAT SHOCK COGNATE 71 KDA PROTEIN
D: BAG FAMILY MOLECULAR CHAPERONE REGULATOR 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)112,86214
Polymers111,8374
Non-polymers1,02510
Water8,935496
1
C: HEAT SHOCK COGNATE 71 KDA PROTEIN
D: BAG FAMILY MOLECULAR CHAPERONE REGULATOR 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,3396
Polymers55,9192
Non-polymers4204
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2700 Å2
ΔGint-3.3 kcal/mol
Surface area22150 Å2
MethodPISA
2
A: HEAT SHOCK COGNATE 71 KDA PROTEIN
B: BAG FAMILY MOLECULAR CHAPERONE REGULATOR 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,5238
Polymers55,9192
Non-polymers6056
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3050 Å2
ΔGint2.7 kcal/mol
Surface area22820 Å2
MethodPISA
Unit cell
Length a, b, c (Å)230.369, 40.538, 116.618
Angle α, β, γ (deg.)90.00, 90.51, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-2003-

HOH

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Components

#1: Protein HEAT SHOCK COGNATE 71 KDA PROTEIN


Mass: 42406.980 Da / Num. of mol.: 2 / Fragment: NUCLEOTIDE BINDING DOMAIN RESIDUES 1-381
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PGEX-6P-1 / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 / Variant (production host): AI / References: UniProt: P11142, EC: 3.6.3.51
#2: Protein BAG FAMILY MOLECULAR CHAPERONE REGULATOR 1


Mass: 13511.571 Da / Num. of mol.: 2 / Fragment: RESIDUES 222 TO 334
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PGEX-6P-1 / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 / Variant (production host): AI / References: UniProt: Q99933
#3: Chemical ChemComp-1SQ / ISOQUINOLIN-1-AMINE / 1-AMINO-ISOQUINOLINE


Mass: 144.173 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H8N2
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 496 / 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: 2.43 Å3/Da / Density % sol: 49.47 %
Description: COMPLETENESS IN INNER SHELL 99.6 PERCENT. DATA COLLECTED PRIOR TO USE OF CC-HALF
Crystal growpH: 8.5
Details: 16-26% (W/V) PEG3350, 0.1 M K-NA TARTRATE, 0.1 M TRIS.HCL PH 8.5 AND 25% (V/V) GLYCEROL

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: BRUKER AXS MICROSTAR / Wavelength: 1.5418
DetectorType: BRUKER PT135 / Detector: CCD / Date: Feb 8, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→58.31 Å / Num. obs: 47003 / % possible obs: 63.7 % / Observed criterion σ(I): 0 / Redundancy: 2.6 % / Biso Wilson estimate: 9.87 Å2 / Rmerge(I) obs: 0.19 / Net I/σ(I): 3.6
Reflection shellResolution: 2→2.05 Å / Redundancy: 1 % / Rmerge(I) obs: 0.82 / Mean I/σ(I) obs: 0.6 / % possible all: 17.9

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Processing

Software
NameVersionClassification
BUSTER2.10.2refinement
SAINTdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1HX1

1hx1


Resolution: 2→58.31 Å / Cor.coef. Fo:Fc: 0.803 / Cor.coef. Fo:Fc free: 0.7151 / SU R Cruickshank DPI: 0.36 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.381 / SU Rfree Blow DPI: 0.252 / SU Rfree Cruickshank DPI: 0.251
RfactorNum. reflection% reflectionSelection details
Rfree0.2605 2329 4.96 %RANDOM
Rwork0.2079 ---
obs0.2105 47002 63.59 %-
Displacement parametersBiso mean: 15.1 Å2
Baniso -1Baniso -2Baniso -3
1--5.4785 Å20 Å22.3093 Å2
2---4.9398 Å20 Å2
3---10.4183 Å2
Refine analyzeLuzzati coordinate error obs: 0.354 Å
Refinement stepCycle: LAST / Resolution: 2→58.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7546 0 70 496 8112
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0097718HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0810419HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2747SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes221HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1139HARMONIC5
X-RAY DIFFRACTIONt_it7718HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.32
X-RAY DIFFRACTIONt_other_torsion18.87
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1048SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact9220SEMIHARMONIC4
LS refinement shellResolution: 2→2.05 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3295 48 5.07 %
Rwork0.2723 899 -
all0.2751 947 -
obs--17.53 %
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)
10.16810.48160.46570.9738-0.04481.51820.0076-0.0915-0.00520.0981-0.0207-0.0340.03760.03790.0131-0.1156-0.0378-0.0474-0.2778-0.06080.1123-39.6029-18.850245.132
20.35120.5016-0.34842.1676-0.1746-0.00620.0046-0.0072-0.0041-0.00730.0018-0.0036-0.0044-0.0142-0.0065-0.01090.0016-0.0954-0.0623-0.00410.0537-40.7552-25.110622.4424
30.0030.2829-0.168300.6317-0.0030.00250.0011-0.0096-0.0059-0.00770.0178-0.0112-0.00090.00520.0111-0.0143-0.004-0.0433-0.02170.0207-8.173-22.555435.2984
40.0427-0.28440.42560.39740.25770.00760.00360.0818-0.0552-0.0348-0.02440.02520.05430.0460.0208-0.0865-0.032-0.0538-0.066-0.02210.0474-22.5932-19.59627.8088
50.00010.0128-0.00550.0230.00240.02660.0001-0.00030.00170.0010.0001-0.0012-0.00220.0023-0.0002-0.00130.0020.0050.00990.00150.00752.529711.817633.6374
60.37690.4432-0.9380-0.7304-0.0167-0.0091-0.05350.0221-0.04650.0130.0224-0.0404-0.0095-0.0039-0.02960.0285-0.0471-0.0303-0.00320.0348-11.12920.402855.0561
70.55020.0301-0.38730.1756-0.0178-0.00110.0093-0.0346-0.01570.0059-0.0153-0.0081-0.00020.00320.006-0.0739-0.0026-0.0154-0.0425-0.03550.0384-13.7718-9.399158.503
80.6466-0.44950.88990.0776-0.7190.01580.0028-0.0051-0.0178-0.02060.0105-0.0091-0.008-0.0013-0.0134-0.04830.0118-0.0078-0.03260.0039-0.0043-5.8125-7.89954.4704
90.12310.45090.28992.7012-0.3910.78950.0252-0.0547-0.02530.1077-0.0367-0.07660.0964-0.020.0114-0.0604-0.0307-0.0447-0.181-0.04490.0265-39.5292-2.2151-5.6162
101.0624-0.31730.4690.25910.04880.05650.00720.0546-0.0761-0.0958-0.03270.0761-0.01630.09310.0254-0.05040.0166-0.0394-0.09740.0006-0.0023-30.4604-4.1745-26.0396
110.00420.2894-0.23640.24210.75810.16630.0013-0.04020.01830.01980.00030.0043-0.0004-0.0026-0.00160.0150.00040.0236-0.05070.00720.0069-10.995716.3310.3716
120.36060.1852-0.5230.52380.3697-0.0093-0.0001-0.0189-0.0504-0.01020.02-0.0068-0.00260.0161-0.02-0.05030.00260.0329-0.0318-0.02440.0243-10.41328.016-1.7482
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|0 - 182}
2X-RAY DIFFRACTION2{A|183 - 229}
3X-RAY DIFFRACTION3{A|230 - 249}
4X-RAY DIFFRACTION4{A|250 - 381}
5X-RAY DIFFRACTION5{B|148 - 152}
6X-RAY DIFFRACTION6{B|153 - 187}
7X-RAY DIFFRACTION7{B|188 - 230}
8X-RAY DIFFRACTION8{B|231 - 260}
9X-RAY DIFFRACTION9{C|4 - 167}
10X-RAY DIFFRACTION10{C|168 - 381}
11X-RAY DIFFRACTION11{D|151 - 192}
12X-RAY DIFFRACTION12{D|193 - 260}

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