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- PDB-2xdu: Structure of HSP90 with small molecule inhibitor bound -

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Basic information

Entry
Database: PDB / ID: 2xdu
TitleStructure of HSP90 with small molecule inhibitor bound
ComponentsHEAT SHOCK PROTEIN HSP 90-ALPHA
KeywordsCHAPERONE
Function / homology
Function and homology information


sperm mitochondrial sheath / sulfonylurea receptor binding / dATP binding / CTP binding / positive regulation of protein polymerization / Scavenging by Class F Receptors / vRNP Assembly / UTP binding / sperm plasma membrane / chaperone-mediated autophagy ...sperm mitochondrial sheath / sulfonylurea receptor binding / dATP binding / CTP binding / positive regulation of protein polymerization / Scavenging by Class F Receptors / vRNP Assembly / UTP binding / sperm plasma membrane / chaperone-mediated autophagy / Rho GDP-dissociation inhibitor binding / Respiratory syncytial virus genome replication / telomerase holoenzyme complex assembly / mitochondrial transport / Uptake and function of diphtheria toxin / 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 / protein import into mitochondrial matrix / dendritic growth cone / TPR domain binding / PIWI-interacting RNA (piRNA) biogenesis / Assembly and release of respiratory syncytial virus (RSV) virions / non-chaperonin molecular chaperone ATPase / protein unfolding / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / positive regulation of cell size / HSF1-dependent transactivation / response to unfolded protein / enzyme-substrate adaptor activity / skeletal muscle contraction / regulation of protein-containing complex assembly / HSF1 activation / Attenuation phase / chaperone-mediated protein complex assembly / neurofibrillary tangle assembly / regulation of postsynaptic membrane neurotransmitter receptor levels / RHOBTB2 GTPase cycle / telomere maintenance via telomerase / axonal growth cone / positive regulation of lamellipodium assembly / nitric oxide metabolic process / eNOS activation / positive regulation of defense response to virus by host / DNA polymerase binding / response to salt stress / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / positive regulation of telomere maintenance via telomerase / Signaling by ERBB2 / cardiac muscle cell apoptotic process / endocytic vesicle lumen / positive regulation of cardiac muscle contraction / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / activation of innate immune response / lysosomal lumen / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / positive regulation of interferon-beta production / ESR-mediated signaling / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / protein tyrosine kinase binding / response to cold / Constitutive Signaling by Overexpressed ERBB2 / AURKA Activation by TPX2 / nitric-oxide synthase regulator activity / VEGFR2 mediated vascular permeability / response to cocaine / ATP-dependent protein folding chaperone / brush border membrane / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / DDX58/IFIH1-mediated induction of interferon-alpha/beta / Signaling by ERBB2 KD Mutants / cellular response to virus / Regulation of actin dynamics for phagocytic cup formation / positive regulation of protein import into nucleus / Regulation of necroptotic cell death / VEGFA-VEGFR2 Pathway / response to estrogen / tau protein binding / histone deacetylase binding / Downregulation of ERBB2 signaling / neuron migration / Chaperone Mediated Autophagy / Aggrephagy / disordered domain specific binding / positive regulation of nitric oxide biosynthetic process / MHC class II protein complex binding / positive regulation of protein catabolic process
Similarity search - Function
Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / Histidine kinase-like ATPase, C-terminal domain / HSP90, C-terminal domain / Heat shock protein Hsp90, N-terminal / Heat shock protein Hsp90 family / Hsp90 protein / Heat Shock Protein 90 / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase ...Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / Histidine kinase-like ATPase, C-terminal domain / HSP90, C-terminal domain / Heat shock protein Hsp90, N-terminal / Heat shock protein Hsp90 family / Hsp90 protein / Heat Shock Protein 90 / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase superfamily / Ribosomal protein S5 domain 2-type fold / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
PYRIMIDIN-2-AMINE / 1-CHLORO-4-METHYLPHTHALAZINE / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / OTHER / Resolution: 1.74 Å
AuthorsMurray, C.W. / Carr, M.G. / Callaghan, O. / Chessari, G. / Congreve, M. / Cowan, S. / Coyle, J.E. / Downham, R. / Figueroa, E. / Frederickson, M. ...Murray, C.W. / Carr, M.G. / Callaghan, O. / Chessari, G. / Congreve, M. / Cowan, S. / Coyle, J.E. / Downham, R. / Figueroa, E. / Frederickson, M. / Graham, B. / McMenamin, R. / OBrien, M.A. / Patel, S. / Phillips, T.R. / Williams, G. / Woodhead, A.J. / Woolford, A.J.A.
CitationJournal: J.Med.Chem. / Year: 2010
Title: Fragment-Based Drug Discovery Applied to Hsp90. Discovery of Two Lead Series with High Ligand Efficiency.
Authors: Murray, C.W. / Carr, M.G. / Callaghan, O. / Chessari, G. / Congreve, M. / Cowan, S. / Coyle, J.E. / Downham, R. / Figueroa, E. / Frederickson, M. / Graham, B. / Mcmenamin, R. / O'Brien, M.A. ...Authors: Murray, C.W. / Carr, M.G. / Callaghan, O. / Chessari, G. / Congreve, M. / Cowan, S. / Coyle, J.E. / Downham, R. / Figueroa, E. / Frederickson, M. / Graham, B. / Mcmenamin, R. / O'Brien, M.A. / Patel, S. / Phillips, T.R. / Williams, G. / Woodhead, A.J. / Woolford, A.J.A.
History
DepositionMay 7, 2010Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 1, 2010Provider: repository / Type: Initial release
Revision 1.1Apr 24, 2013Group: Other / Structure summary / Version format compliance
Revision 1.2May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / 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

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Assembly

Deposited unit
A: HEAT SHOCK PROTEIN HSP 90-ALPHA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,8015
Polymers26,4251
Non-polymers3764
Water4,161231
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)67.013, 90.725, 98.735
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11A-2036-

HOH

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Components

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Protein , 1 types, 1 molecules A

#1: Protein HEAT SHOCK PROTEIN HSP 90-ALPHA / HEAT SHOCK 86 KDA / HSP 86 / HSP86 / RENAL CARCINOMA ANTIGEN NY-REN-38 / HSP90


Mass: 26424.840 Da / Num. of mol.: 1 / Fragment: RESIDUES 14-224
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P07900

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Non-polymers , 5 types, 235 molecules

#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-LGA / PYRIMIDIN-2-AMINE


Mass: 95.103 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H5N3
#5: Chemical ChemComp-MT0 / 1-CHLORO-4-METHYLPHTHALAZINE


Mass: 178.618 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H7ClN2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 231 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.84 Å3/Da / Density % sol: 56.68 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Wavelength: 1.5418
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.74→27.56 Å / Num. obs: 31183 / % possible obs: 96.6 % / Observed criterion σ(I): 0 / Redundancy: 3.9 % / Rmerge(I) obs: 0.04

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Processing

SoftwareName: REFMAC / Version: 5.6.0062 / Classification: refinement
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 1.74→67.42 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.95 / SU B: 4.407 / SU ML: 0.073 / Cross valid method: THROUGHOUT / ESU R: 0.103 / ESU R Free: 0.101 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. ATOM RECORD CONTAINS SUM OF TLS AND RESIDUAL B FACTORS.
RfactorNum. reflection% reflectionSelection details
Rfree0.222 1522 5 %RANDOM
Rwork0.19629 ---
obs0.19757 29145 98.35 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 31.686 Å2
Baniso -1Baniso -2Baniso -3
1--0.11 Å20 Å20 Å2
2---0.16 Å20 Å2
3---0.27 Å2
Refinement stepCycle: LAST / Resolution: 1.74→67.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1635 0 24 231 1890
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0221684
X-RAY DIFFRACTIONr_bond_other_d0.0020.021131
X-RAY DIFFRACTIONr_angle_refined_deg1.2961.9562268
X-RAY DIFFRACTIONr_angle_other_deg0.8922.9912772
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8785207
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.85625.13574
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.04715310
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.901157
X-RAY DIFFRACTIONr_chiral_restr0.0850.2259
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.021847
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02329
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.741→1.786 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.327 106 -
Rwork0.351 1917 -
obs--88.73 %
Refinement TLS params.Method: refined / Origin x: 0.0378 Å / Origin y: 14.8719 Å / Origin z: 20.1576 Å
111213212223313233
T0.0505 Å20.003 Å20.0116 Å2-0.0081 Å2-0.011 Å2--0.0415 Å2
L2.1742 °20.6563 °20.1621 °2-1.2789 °2-0.5391 °2--1.9718 °2
S0.0012 Å °0.0899 Å °-0.0185 Å °-0.0033 Å °0.0133 Å °0.0257 Å °-0.0175 Å °0.0538 Å °-0.0145 Å °

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