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- PDB-5mks: HSP72-NBD bound to compound TCI 8 - Tyr15 in down-conformation -

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Basic information

Entry
Database: PDB / ID: 5mks
TitleHSP72-NBD bound to compound TCI 8 - Tyr15 in down-conformation
ComponentsHeat shock 70 kDa protein 1A
KeywordsCHAPERONE / Irreversible Inhibitor / Lysine modification
Function / homology
Function and homology information


positive regulation of endoribonuclease activity / denatured protein binding / cellular heat acclimation / death receptor agonist activity / negative regulation of inclusion body assembly / Viral RNP Complexes in the Host Cell Nucleus / positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway / C3HC4-type RING finger domain binding / positive regulation of microtubule nucleation / ATP-dependent protein disaggregase activity ...positive regulation of endoribonuclease activity / denatured protein binding / cellular heat acclimation / death receptor agonist activity / negative regulation of inclusion body assembly / Viral RNP Complexes in the Host Cell Nucleus / positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway / C3HC4-type RING finger domain binding / positive regulation of microtubule nucleation / ATP-dependent protein disaggregase activity / misfolded protein binding / regulation of mitotic spindle assembly / negative regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / positive regulation of tumor necrosis factor-mediated signaling pathway / transcription regulator inhibitor activity / aggresome / lysosomal transport / cellular response to steroid hormone stimulus / mRNA catabolic process / regulation of protein ubiquitination / chaperone cofactor-dependent protein refolding / HSF1-dependent transactivation / response to unfolded protein / negative regulation of extrinsic apoptotic signaling pathway in absence of ligand / chaperone-mediated protein complex assembly / Regulation of HSF1-mediated heat shock response / Attenuation phase / cellular response to unfolded protein / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / ATP metabolic process / protein folding chaperone / inclusion body / negative regulation of protein ubiquitination / heat shock protein binding / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / centriole / positive regulation of RNA splicing / positive regulation of erythrocyte differentiation / AUF1 (hnRNP D0) binds and destabilizes mRNA / positive regulation of interleukin-8 production / G protein-coupled receptor binding / ATP-dependent protein folding chaperone / negative regulation of transforming growth factor beta receptor signaling pathway / PKR-mediated signaling / negative regulation of cell growth / histone deacetylase binding / transcription corepressor activity / disordered domain specific binding / unfolded protein binding / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / virus receptor activity / positive regulation of NF-kappaB transcription factor activity / cellular response to heat / cellular response to oxidative stress / protein refolding / vesicle / ficolin-1-rich granule lumen / receptor ligand activity / protein stabilization / blood microparticle / nuclear speck / ribonucleoprotein complex / cadherin binding / negative regulation of cell population proliferation / focal adhesion / signaling receptor binding / centrosome / ubiquitin protein ligase binding / Neutrophil degranulation / positive regulation of gene expression / negative regulation of apoptotic process / perinuclear region of cytoplasm / enzyme binding / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum / ATP hydrolysis activity / protein-containing complex / mitochondrion / RNA binding / extracellular space / extracellular exosome / extracellular region / nucleoplasm / ATP binding / nucleus / plasma membrane / cytoplasm / cytosol
Similarity search - Function
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 ...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 / ATPase, nucleotide binding domain / Nucleotidyltransferase; domain 5 / Alpha-Beta Complex / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-TI8 / Heat shock 70 kDa protein 1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.99 Å
AuthorsPettinger, J. / Westwood, I.M. / Cronin, N. / Le Bihan, Y.-V. / Van Montfort, R.L.M.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
Cancer Research UKC309/A8274 United Kingdom
Cancer Research UKC309/A11566 United Kingdom
CitationJournal: Angew. Chem. Int. Ed. Engl. / Year: 2017
Title: An Irreversible Inhibitor of HSP72 that Unexpectedly Targets Lysine-56.
Authors: Pettinger, J. / Le Bihan, Y.V. / Widya, M. / van Montfort, R.L. / Jones, K. / Cheeseman, M.D.
History
DepositionDec 5, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 1, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 29, 2017Group: Database references
Revision 1.2May 1, 2024Group: 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: Heat shock 70 kDa protein 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,6852
Polymers43,1961
Non-polymers4891
Water6,954386
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area16830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.637, 83.672, 99.210
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Heat shock 70 kDa protein 1A / Heat shock 70 kDa protein 1 / HSP70.1


Mass: 43195.902 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSPA1A, HSPA1, HSX70 / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: P0DMV8
#2: Chemical ChemComp-TI8 / 3-[(2~{R},3~{S},4~{R},5~{R})-5-[6-azanyl-8-[(4-chlorophenyl)methylamino]purin-9-yl]-3,4-bis(oxidanyl)oxolan-2-yl]propyl prop-2-enoate


Mass: 488.924 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H25ClN6O5
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 386 / 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: 2.24 Å3/Da / Density % sol: 45.1 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / pH: 8.8
Details: 16% w/v PEG-3350, 0.02 M citric acid, 0.08 M BIS-TRIS propane. Inhibitor was pre-incubated with protein prior to co-crystallisation.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-X / Wavelength: 1.5419 Å
DetectorType: DECTRIS PILATUS 300K / Detector: PIXEL / Date: Oct 28, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5419 Å / Relative weight: 1
ReflectionResolution: 1.99→46.64 Å / Num. obs: 27315 / % possible obs: 99.6 % / Redundancy: 10.8 % / Biso Wilson estimate: 26.55 Å2 / CC1/2: 0.991 / Rpim(I) all: 0.068 / Net I/σ(I): 7.9
Reflection shellResolution: 1.99→2.04 Å / Redundancy: 5.3 % / Mean I/σ(I) obs: 1 / CC1/2: 0.3 / Rpim(I) all: 0.998 / % possible all: 97.9

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Processing

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

Resolution: 1.99→42.67 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.917 / SU R Cruickshank DPI: 0.197 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.224 / SU Rfree Blow DPI: 0.187 / SU Rfree Cruickshank DPI: 0.178
RfactorNum. reflection% reflectionSelection details
Rfree0.255 1362 5.02 %RANDOM
Rwork0.201 ---
obs0.204 27135 99.2 %-
Displacement parametersBiso mean: 37.88 Å2
Baniso -1Baniso -2Baniso -3
1-7.534 Å20 Å20 Å2
2---0.7778 Å20 Å2
3----6.7563 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: 1 / Resolution: 1.99→42.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2905 0 31 388 3324
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.013003HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.074074HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1044SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes81HARMONIC2
X-RAY DIFFRACTIONt_gen_planes463HARMONIC5
X-RAY DIFFRACTIONt_it3003HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.13
X-RAY DIFFRACTIONt_other_torsion16.9
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion410SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies4HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3864SEMIHARMONIC4
LS refinement shellResolution: 1.99→2.06 Å / Rfactor Rfree error: 0 / Total num. of bins used: 14
RfactorNum. reflection% reflection
Rfree0.242 147 5.3 %
Rwork0.224 2624 -
all0.225 2771 -
obs--98.16 %
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)
12.6604-0.4987-1.01760.57720.65552.3797-0.0546-0.19580.5442-0.08840.072-0.0990.0060.2026-0.0174-0.11540.00320.0218-0.1146-0.03920.0186-9.2463-0.7519-3.3564
21.8743-1.29780.8322.4065-1.42671.5535-0.2578-0.54420.34290.44050.2864-0.1072-0.1666-0.3463-0.0286-0.06910.0510.01130.0422-0.152-0.1514-16.0289-6.136216.451
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{A|3 - 229}
2X-RAY DIFFRACTION2{A|230 - 383}

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