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- PDB-7dmc: Dipyridamole binds to the N-terminal domain of human Hsp90A -

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Basic information

Entry
Database: PDB / ID: 7dmc
TitleDipyridamole binds to the N-terminal domain of human Hsp90A
ComponentsHeat shock protein HSP 90-alphaHeat shock response
KeywordsCHAPERONE / ATP binding domain / Hsp90 / Dipyridamole
Function / homology
Function and homology information


sperm mitochondrial sheath / dATP binding / Scavenging by Class F Receptors / sulfonylurea receptor binding / CTP binding / positive regulation of protein polymerization / vRNP Assembly / UTP binding / sperm plasma membrane / positive regulation of tau-protein kinase activity ...sperm mitochondrial sheath / dATP binding / Scavenging by Class F Receptors / sulfonylurea receptor binding / CTP binding / positive regulation of protein polymerization / vRNP Assembly / UTP binding / sperm plasma membrane / positive regulation of tau-protein kinase activity / protein insertion into mitochondrial outer membrane / chaperone-mediated autophagy / telomerase holoenzyme complex assembly / Rho GDP-dissociation inhibitor binding / Uptake and function of diphtheria toxin / mitochondrial transport / Drug-mediated inhibition of ERBB2 signaling / Resistance of ERBB2 KD mutants to trastuzumab / Resistance of ERBB2 KD mutants to sapitinib / Resistance of ERBB2 KD mutants to tesevatinib / Resistance of ERBB2 KD mutants to neratinib / Resistance of ERBB2 KD mutants to osimertinib / Resistance of ERBB2 KD mutants to afatinib / Resistance of ERBB2 KD mutants to AEE788 / Resistance of ERBB2 KD mutants to lapatinib / Drug resistance in ERBB2 TMD/JMD mutants / PIWI-interacting RNA (piRNA) biogenesis / TPR domain binding / non-chaperonin molecular chaperone ATPase / regulation of postsynaptic membrane neurotransmitter receptor levels / dendritic growth cone / Sema3A PAK dependent Axon repulsion / skeletal muscle contraction / regulation of protein ubiquitination / positive regulation of cell size / protein unfolding / HSF1-dependent transactivation / telomere maintenance via telomerase / response to unfolded protein / HSF1 activation / chaperone-mediated protein complex assembly / regulation of protein-containing complex assembly / Attenuation phase / RHOBTB2 GTPase cycle / positive regulation of lamellipodium assembly / eNOS activation / DNA polymerase binding / axonal growth cone / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / positive regulation of cardiac muscle contraction / Signaling by ERBB2 / cardiac muscle cell apoptotic process / Recruitment of mitotic centrosome proteins and complexes / positive regulation of telomerase activity / response to salt stress / positive regulation of defense response to virus by host / endocytic vesicle lumen / Recruitment of NuMA to mitotic centrosomes / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / Anchoring of the basal body to the plasma membrane / protein tyrosine kinase binding / response to cold / activation of innate immune response / positive regulation of interferon-beta production / nitric-oxide synthase regulator activity / lysosomal lumen / Constitutive Signaling by Overexpressed ERBB2 / ESR-mediated signaling / AURKA Activation by TPX2 / VEGFR2 mediated vascular permeability / response to cocaine / brush border membrane / ATP-dependent protein folding chaperone / Signaling by ERBB2 TMD/JMD mutants / neuron migration / Constitutive Signaling by EGFRvIII / DDX58/IFIH1-mediated induction of interferon-alpha/beta / Signaling by ERBB2 ECD mutants / tau protein binding / Signaling by ERBB2 KD Mutants / Regulation of necroptotic cell death / Regulation of actin dynamics for phagocytic cup formation / Downregulation of ERBB2 signaling / cellular response to virus / VEGFA-VEGFR2 Pathway / Aggrephagy / Chaperone Mediated Autophagy / positive regulation of protein import into nucleus / response to estrogen / histone deacetylase binding / positive regulation of protein catabolic process / The role of GTSE1 in G2/M progression after G2 checkpoint / regulation of protein localization / positive regulation of nitric oxide biosynthetic process / disordered domain specific binding / Regulation of PLK1 Activity at G2/M Transition / unfolded protein binding / melanosome
Similarity search - Function
Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / HSP90, C-terminal domain / Heat shock protein Hsp90, N-terminal / Heat shock protein Hsp90 family / Hsp90 protein / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase / Histidine kinase/HSP90-like ATPase superfamily / Ribosomal protein S5 domain 2-type fold
Similarity search - Domain/homology
Chem-H9F / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.34 Å
AuthorsShi, L. / Zhou, C. / Zhong, Y. / Gao, J. / Zhou, H. / Zhang, N.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Biochem Pharmacol / Year: 2022
Title: Dipyridamole interacts with the N-terminal domain of HSP90 and antagonizes the function of the chaperone in multiple cancer cell lines.
Authors: Gao, J. / Zhou, C. / Zhong, Y. / Shi, L. / Luo, X. / Su, H. / Li, M. / Xu, Y. / Zhang, N. / Zhou, H.
History
DepositionDec 3, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 8, 2021Provider: repository / Type: Initial release
Revision 1.1Dec 28, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._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
Revision 1.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Heat shock protein HSP 90-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,0176
Polymers23,3931
Non-polymers6245
Water91951
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area130 Å2
ΔGint-12 kcal/mol
Surface area10750 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.489, 89.937, 99.067
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11A-449-

HOH

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Components

#1: Protein Heat shock protein HSP 90-alpha / Heat shock response / Heat shock 86 kDa / HSP86 / Lipopolysaccharide-associated protein 2 / LPS-associated protein 2 / ...Heat shock 86 kDa / HSP86 / Lipopolysaccharide-associated protein 2 / LPS-associated protein 2 / Renal carcinoma antigen NY-REN-38


Mass: 23392.516 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSP90AA1, HSP90A, HSPC1, HSPCA / Production host: Escherichia coli (E. coli) / References: UniProt: P07900
#2: Chemical ChemComp-H9F / 2-[[2-[bis(2-hydroxyethyl)amino]-4,8-di(piperidin-1-yl)pyrimido[5,4-d]pyrimidin-6-yl]-(2-hydroxyethyl)amino]ethanol / Dipyridamole


Mass: 504.626 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H40N8O4 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, inhibitor*YM
#3: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 51 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 3.23 Å3/Da / Density % sol: 61.64 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / Details: 0.1 M Tris pH8.7, 0.2M MgCl2, 22% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.97852 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Nov 30, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97852 Å / Relative weight: 1
ReflectionResolution: 2.34→36.95 Å / Num. obs: 13286 / % possible obs: 97.4 % / Redundancy: 2 % / CC1/2: 1 / Rmerge(I) obs: 0.01 / Rrim(I) all: 0.013 / Net I/σ(I): 32.05
Reflection shellResolution: 2.34→2.42 Å / Rmerge(I) obs: 0.06314 / Num. unique obs: 1344 / CC1/2: 0.988 / Rpim(I) all: 0.06314 / Rrim(I) all: 0.08929

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Processing

Software
NameVersionClassification
XSCALEdata scaling
REFMAC5.8.0258refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3T0H

3t0h


Resolution: 2.34→36.95 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.916 / SU B: 6.104 / SU ML: 0.145 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.269 / ESU R Free: 0.217 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2438 680 5.1 %RANDOM
Rwork0.2029 ---
obs0.2051 12625 97.38 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 105.83 Å2 / Biso mean: 44.168 Å2 / Biso min: 25.7 Å2
Baniso -1Baniso -2Baniso -3
1-0.39 Å20 Å2-0 Å2
2--0.6 Å20 Å2
3----0.99 Å2
Refinement stepCycle: final / Resolution: 2.34→36.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1644 0 40 51 1735
Biso mean--46.46 42.77 -
Num. residues----209
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0131709
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171612
X-RAY DIFFRACTIONr_angle_refined_deg1.6521.6382303
X-RAY DIFFRACTIONr_angle_other_deg1.3291.5763755
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.6375208
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.16523.90282
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.42815312
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.645157
X-RAY DIFFRACTIONr_chiral_restr0.0790.2231
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.021876
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02331
LS refinement shellResolution: 2.34→2.4 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.305 49 -
Rwork0.209 926 -
obs--99.69 %

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