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- PDB-5aqf: Fragment-based screening of HSP70 sheds light on the functional r... -

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Basic information

Entry
Database: PDB / ID: 5aqf
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 / ATP metabolic process / protein folding chaperone / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / heat shock protein binding / cellular response to starvation / mRNA Splicing - Major Pathway / lysosomal lumen / G protein-coupled receptor binding / AUF1 (hnRNP D0) binds and destabilizes mRNA / spliceosomal complex / ATP-dependent protein folding chaperone / 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 / secretory granule lumen / Interleukin-4 and Interleukin-13 signaling / 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
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: 1.88 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: 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 1.2Jan 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
C: HEAT SHOCK COGNATE 71 KDA PROTEIN
D: BAG FAMILY MOLECULAR CHAPERONE REGULATOR 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)113,72120
Polymers111,8374
Non-polymers1,88416
Water16,754930
1
A: HEAT SHOCK COGNATE 71 KDA PROTEIN
B: BAG FAMILY MOLECULAR CHAPERONE REGULATOR 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)57,04512
Polymers55,9192
Non-polymers1,12610
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4780 Å2
ΔGint7.3 kcal/mol
Surface area22700 Å2
MethodPISA
2
C: HEAT SHOCK COGNATE 71 KDA PROTEIN
D: BAG FAMILY MOLECULAR CHAPERONE REGULATOR 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,6768
Polymers55,9192
Non-polymers7586
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3850 Å2
ΔGint7.6 kcal/mol
Surface area22370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)230.729, 40.740, 116.690
Angle α, β, γ (deg.)90.00, 91.16, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-2105-

HOH

21D-2014-

HOH

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Components

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Protein , 2 types, 4 molecules ACBD

#1: Protein HEAT SHOCK COGNATE 71 KDA PROTEIN / HEAT SHOCK 70 KDA PROTEIN 8 / LIPOPOLYSACCHARIDE-ASSOCIATED PROTEIN 1 / LAP-1 / LPS-ASSOCIATED PROTEIN 1


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) / 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.: 2 / Fragment: RESIDUES 222-334
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 / Variant (production host): AI / References: UniProt: Q99933

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Non-polymers , 4 types, 946 molecules

#3: Chemical ChemComp-ADN / ADENOSINE / Adenosine


Mass: 267.241 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H13N5O4
#4: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-TRS / 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / TRIS BUFFER / Tris


Mass: 122.143 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H12NO3 / Comment: pH buffer*YM
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 930 / 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: 2.5 Å3/Da / Density % sol: 51 % / Description: NONE
Crystal growpH: 8.5
Details: HSC70/BAG1 COMPLEX AT 10 MG/ML INCUBATED WITH 5 MM ADENOSINE, MIXED 1:1 WITH 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: I02 / Wavelength: 0.9796
DetectorType: ADSC CCD / Detector: CCD / Date: May 21, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9796 Å / Relative weight: 1
ReflectionResolution: 1.88→82.87 Å / Num. obs: 76667 / % possible obs: 86.2 % / Observed criterion σ(I): 0 / Redundancy: 3.4 % / Biso Wilson estimate: 27.37 Å2 / Rmerge(I) obs: 0.1 / Net I/σ(I): 6.2
Reflection shellResolution: 1.88→1.92 Å / Redundancy: 2.3 % / Rmerge(I) obs: 0.72 / Mean I/σ(I) obs: 0.8 / % possible all: 45.8

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Processing

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

1hx1


Resolution: 1.88→82.87 Å / Cor.coef. Fo:Fc: 0.921 / Cor.coef. Fo:Fc free: 0.9009 / SU R Cruickshank DPI: 0.153 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.165 / SU Rfree Blow DPI: 0.143 / SU Rfree Cruickshank DPI: 0.138
Details: IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2076 3821 4.98 %RANDOM
Rwork0.1695 ---
obs0.1714 76660 85.74 %-
Displacement parametersBiso mean: 34.95 Å2
Baniso -1Baniso -2Baniso -3
1-0.1263 Å20 Å214.9133 Å2
2--2.6355 Å20 Å2
3----2.7618 Å2
Refine analyzeLuzzati coordinate error obs: 0.232 Å
Refinement stepCycle: LAST / Resolution: 1.88→82.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7599 0 126 930 8655
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.017874HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0110631HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2835SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes224HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1161HARMONIC5
X-RAY DIFFRACTIONt_it7874HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.02
X-RAY DIFFRACTIONt_other_torsion15.8
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1067SEMIHARMONIC5
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_contact9983SEMIHARMONIC4
LS refinement shellResolution: 1.88→1.93 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2116 139 4.69 %
Rwork0.1984 2825 -
all0.199 2964 -
obs--45.16 %
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)
11.03890.38110.41451.35380.43891.2720.0989-0.0689-0.04510.1333-0.0413-0.08040.0850.0043-0.0577-0.0622-0.0172-0.0321-0.0802-0.0125-0.0083-40.2669-18.896845.4485
21.5692-0.05720.48070.52-0.01870.39060.03620.2008-0.0953-0.075-0.030.1169-0.00520.0016-0.0062-0.0248-0.0039-0.0135-0.0111-0.0378-0.0624-25.4758-21.267627.6434
31.28651.3447-2.17391.6567-2.11114.84810.0612-0.07690.2326-0.0470.01840.1093-0.088-0.0823-0.0796-0.04620.02120.0135-0.0254-0.06020.0106-10.71091.281552.9019
41.15610.1763-1.13590.7326-0.44083.87990.0062-0.24210.1169-0.01830.0210.11890.1667-0.1166-0.0272-0.05130.0012-0.00020.046-0.04790.0098-14.3944-9.43758.2568
51.29970.5293-0.77720.8464-0.70881.63010.0337-0.1930.1315-0.0573-0.0454-0.01110.0450.13670.0117-0.0489-0.0057-0.0001-0.0387-0.0286-0.0735-6.3814-8.195954.6252
61.18910.76540.75293.17820.62081.55690.155-0.0836-0.03780.4706-0.2023-0.1770.1238-0.10010.0473-0.0621-0.0295-0.0287-0.1208-0.0119-0.0661-40.6973-1.5216-6.8843
71.86610.03830.40820.40010.04790.23040.00670.1834-0.0924-0.0739-0.00350.0467-0.0360.0164-0.0032-0.02070.0004-0.0084-0.0119-0.0246-0.0405-28.5891-4.0992-26.6032
80.80030.8128-0.39351.1897-1.46542.28280.0668-0.1920.15260.1186-0.00010.0334-0.0994-0.0549-0.06670.0041-0.00070.0357-0.0736-0.064-0.0164-11.027317.9458-3.3162
90.07290.2484-0.20851.7824-0.66342.69670.006-0.13850.04150.01570.00020.04080.1679-0.1171-0.0062-0.06230.00460.00230.0461-0.0213-0.0045-13.59727.33062.3371
101.9856-0.1819-0.35880.4783-0.22141.94360.0337-0.29630.0856-0.050.0325-0.16270.04760.1573-0.0661-0.0515-0.0324-0.0009-0.0666-0.0647-0.0247-5.67348.9574-3.1053
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|0 - 182}
2X-RAY DIFFRACTION2{A|183 - 381}
3X-RAY DIFFRACTION3{B|149 - 187}
4X-RAY DIFFRACTION4{B|188 - 230}
5X-RAY DIFFRACTION5{B|231 - 261}
6X-RAY DIFFRACTION6{C|0 - 182}
7X-RAY DIFFRACTION7{C|183 - 381}
8X-RAY DIFFRACTION8{D|150 - 187}
9X-RAY DIFFRACTION9{D|188 - 230}
10X-RAY DIFFRACTION10{D|231 - 261}

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