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Basic information

Entry
Database: PDB / ID: 5aqt
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 / protein transmembrane import into intracellular organelle / negative regulation of supramolecular fiber organization / positive regulation of protein refolding / prostaglandin binding / chaperone-mediated autophagy translocation complex disassembly / slow axonal transport / clathrin-uncoating ATPase activity / positive regulation of lysosomal membrane permeability ...lumenal side of lysosomal membrane / regulation of protein import / protein transmembrane import into intracellular organelle / negative regulation of supramolecular fiber organization / positive regulation of protein refolding / prostaglandin binding / chaperone-mediated autophagy translocation complex disassembly / slow axonal transport / clathrin-uncoating ATPase activity / positive regulation of lysosomal membrane permeability / lysosomal matrix / A1 adenosine receptor binding / late endosomal microautophagy / protein carrier chaperone / response to nickel cation / clathrin-sculpted gamma-aminobutyric acid transport vesicle membrane / Respiratory syncytial virus genome transcription / Lipophagy / GABA synthesis, release, reuptake and degradation / protein targeting to lysosome involved in chaperone-mediated autophagy / adenyl-nucleotide exchange factor activity / response to odorant / positive regulation by host of viral genome replication / synaptic vesicle uncoating / C3HC4-type RING finger domain binding / positive regulation of smooth muscle cell apoptotic process / clathrin coat disassembly / negative regulation of NLRP3 inflammasome complex assembly / ATP-dependent protein disaggregase activity / CHL1 interactions / regulation of protein complex stability / photoreceptor ribbon synapse / maintenance of postsynaptic specialization structure / membrane organization / glycinergic synapse / Prp19 complex / presynaptic cytosol / protein folding chaperone complex / positive regulation of mRNA splicing, via spliceosome / postsynaptic specialization membrane / intermediate filament / regulation of postsynapse organization / negative regulation of cardiac muscle cell apoptotic process / Lysosome Vesicle Biogenesis / chaperone-mediated autophagy / postsynaptic cytosol / cellular response to steroid hormone stimulus / Golgi Associated Vesicle Biogenesis / phosphatidylserine binding / non-chaperonin molecular chaperone ATPase / positive regulation of proteolysis / chaperone cofactor-dependent protein refolding / HSF1-dependent transactivation / response to unfolded protein / estrous cycle / autophagosome / Regulation of HSF1-mediated heat shock response / regulation of protein-containing complex assembly / Attenuation phase / Protein methylation / ATP metabolic process / positive regulation of phagocytosis / skeletal muscle tissue development / forebrain development / protein folding chaperone / heat shock protein binding / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / cellular response to cadmium ion / photoreceptor inner segment / cellular response to starvation / lysosomal lumen / mRNA Splicing - Major Pathway / cerebellum development / response to activity / dendritic shaft / kidney development / AUF1 (hnRNP D0) binds and destabilizes mRNA / response to progesterone / G protein-coupled receptor binding / ATP-dependent protein folding chaperone / spliceosomal complex / Late endosomal microautophagy / peptide binding / regulation of protein stability / PKR-mediated signaling / terminal bouton / ADP binding / mRNA splicing, via spliceosome / Chaperone Mediated Autophagy / cellular response to hydrogen peroxide / positive regulation of T cell mediated cytotoxicity / G1/S transition of mitotic cell cycle / protein import into nucleus / unfolded protein binding / melanosome / late endosome / protein folding / synaptic vesicle / response to estradiol / MHC class II protein complex binding
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 / Nucleotidyltransferase; domain 5 / Ubiquitin domain profile. / Ubiquitin-like domain / Ubiquitin-like domain superfamily / Alpha-Beta Complex / Up-down Bundle / 2-Layer Sandwich / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-5P7 / 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
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 1.1Sep 13, 2017Group: Data collection / Database references / Category: citation / citation_author / diffrn_detector
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 / _diffrn_detector.type
Revision 1.2Jan 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,02512
Polymers55,9192
Non-polymers1,10610
Water3,783210
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4180 Å2
ΔGint3.8 kcal/mol
Surface area22190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)115.237, 40.840, 131.959
Angle α, β, γ (deg.)90.00, 117.99, 90.00
Int Tables number5
Space group name H-MC121

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein HEAT SHOCK COGNATE 71 KDA PROTEIN / HEAT SHOCK 70 KDA PROTEIN 8 / LIPOPOLYSACCHARIDE-ASSOCIATED PROTEIN 1 / LAP-1 / LPS-ASSOCIATED ...HEAT SHOCK 70 KDA PROTEIN 8 / LIPOPOLYSACCHARIDE-ASSOCIATED PROTEIN 1 / LAP-1 / LPS-ASSOCIATED PROTEIN 1 / HEAT SHOCK 70 KDA PROT EIN 8 / LIPOPOLYSACCHARIDE-ASSOCIATED PROTEIN 1 / LAP-1 / LPS-ASSOCIA TED PROTEIN 1


Mass: 42406.980 Da / Num. of mol.: 1 / Fragment: NUCLEOTIDE BINDING DOMAIN, UNP 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 / BAG-1 / BCL-2-ASSOCIATED ATHANOGENE 1


Mass: 13511.571 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 222-334
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

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Non-polymers , 5 types, 220 molecules

#3: Chemical ChemComp-5P7 / (1S,2R,3R,5R)-3-(hydroxymethyl)-5-(quinazolin-4-ylamino)cyclopentane-1,2-diol


Mass: 275.303 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H17N3O3
#4: Chemical ChemComp-TRS / 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / TRIS BUFFER


Mass: 122.143 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H12NO3 / Comment: pH buffer*YM
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C3H8O3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 210 / 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: 2.45 Å3/Da / Density % sol: 49.83 % / Description: NONE
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: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.92
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Sep 29, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92 Å / Relative weight: 1
ReflectionResolution: 1.9→58.26 Å / Num. obs: 36309 / % possible obs: 83.9 % / Observed criterion σ(I): 0 / Redundancy: 3 % / Biso Wilson estimate: 28.21 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 9.3
Reflection shellResolution: 1.9→1.94 Å / Redundancy: 3.2 % / Rmerge(I) obs: 0.61 / Mean I/σ(I) obs: 1.7 / % possible all: 70.6

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Processing

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

1hx1


Resolution: 1.9→58.26 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.917 / SU R Cruickshank DPI: 0.163 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.164 / SU Rfree Blow DPI: 0.149 / SU Rfree Cruickshank DPI: 0.149
RfactorNum. reflection% reflectionSelection details
Rfree0.2224 1784 4.92 %RANDOM
Rwork0.1803 ---
obs0.1823 36291 83.73 %-
Displacement parametersBiso mean: 40.54 Å2
Baniso -1Baniso -2Baniso -3
1--3.7928 Å20 Å2-1.7948 Å2
2--3.4867 Å20 Å2
3---0.3061 Å2
Refine analyzeLuzzati coordinate error obs: 0.236 Å
Refinement stepCycle: LAST / Resolution: 1.9→58.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3755 0 72 210 4037
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.013887HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.045254HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1364SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes108HARMONIC2
X-RAY DIFFRACTIONt_gen_planes576HARMONIC5
X-RAY DIFFRACTIONt_it3887HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.73
X-RAY DIFFRACTIONt_other_torsion16.52
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion526SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies1HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4572SEMIHARMONIC4
LS refinement shellResolution: 1.9→1.96 Å / Total num. of bins used: 18
RfactorNum. reflection% reflection
Rfree0.2413 108 4.31 %
Rwork0.2575 2400 -
all0.2569 2508 -
obs--70.6 %
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)
11.4161-0.00160.61623.0516-0.4922.22960.14240.08420.1005-0.1382-0.2872-0.22170.0620.24630.14480.08030.1622-0.07-0.08320.0186-0.191973.94680.0068138.3834
20.9820.10930.65791.3516-0.19343.5977-0.00650.28440.0701-0.3603-0.0762-0.083-0.05490.08860.08270.11980.1626-0.0478-0.05120.0179-0.182567.9234-2.0077127.3182
30.9129-0.56010.82323.30060.89576.78790.09970.4954-0.0394-0.2757-0.0390.2458-0.2312-0.3351-0.06070.02630.1653-0.12660.10140.0128-0.169649.94365.504130.893
40.6799-0.3628-0.78431.74871.05451.770.10050.0214-0.0011-0.243-0.16890.3451-0.13150.06880.0683-0.00310.0441-0.0527-0.0737-0.0110.005658.60073.1671164.1274
51.3588-0.72070.16651.198-0.57622.93820.17340.153-0.072-0.182-0.12050.1368-0.2916-0.532-0.0529-0.0250.1411-0.0939-0.0573-0.0213-0.11454.32171.3137154.5465
62.5972-0.92870.21370.7102-1.41683.795-0.0039-0.1479-0.0843-0.25290.15460.32670.148-0.5313-0.15070.02180.1116-0.17110.0681-0.0343-0.113948.3666-2.3331136.2295
7-0.1383-0.68690.09330-0.00320.1383-0.0172-0.09430.05560.0320.00140.0715-0.0236-0.05450.01580.00630.0664-0.0322-0.0677-0.02940.076153.9565-29.6255175.4842
85.98162.2456-1.38341.1923-0.89210.8264-0.01910.0867-0.1348-0.0228-0.0352-0.04710.14440.13210.0543-0.01710.0626-0.0349-0.0395-0.03570.030781.42-18.7593162.8913
94.65480.7433-1.48392.2185-0.43131.07470.04790.07680.0402-0.0995-0.0556-0.06080.02320.09340.0078-0.02260.0372-0.0651-0.01270.0055-0.079977.7549-10.5499160.5866
103.13371.0692-0.56611.68460.16761.6450.0859-0.1026-0.02030.0335-0.0983-0.1025-0.04420.31020.01240.03010.0439-0.0595-0.02150.0251-0.019876.4709-12.0465169.1327
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|1 - 115}
2X-RAY DIFFRACTION2{A|116 - 182}
3X-RAY DIFFRACTION3{A|183 - 229}
4X-RAY DIFFRACTION4{A|230 - 249}
5X-RAY DIFFRACTION5{A|250 - 343}
6X-RAY DIFFRACTION6{A|344 - 381}
7X-RAY DIFFRACTION7{B|146 - 152}
8X-RAY DIFFRACTION8{B|153 - 192}
9X-RAY DIFFRACTION9{B|193 - 230}
10X-RAY DIFFRACTION10{B|231 - 260}

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