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

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Basic information

Entry
Database: PDB / ID: 2xhx
TitleStructure of HSP90 with small molecule inhibitor bound
ComponentsHEAT SHOCK PROTEIN HSP 90-ALPHA
KeywordsCHAPERONE / HSP90 / ATP BINDING DOMAIN / N-TERMINAL DOMAIN / STRESS RESPONSE
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 / telomere maintenance via telomerase / Attenuation phase / chaperone-mediated protein complex assembly / axonal growth cone / neurofibrillary tangle assembly / regulation of postsynaptic membrane neurotransmitter receptor levels / RHOBTB2 GTPase cycle / positive regulation of lamellipodium assembly / nitric oxide metabolic process / eNOS activation / positive regulation of defense response to virus by host / DNA polymerase binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / response to salt stress / 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 / response to cold / protein tyrosine kinase binding / 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 / Regulation of necroptotic cell death / positive regulation of protein import into nucleus / VEGFA-VEGFR2 Pathway / response to estrogen / tau protein binding / Downregulation of ERBB2 signaling / histone deacetylase binding / Chaperone Mediated Autophagy / neuron migration / Aggrephagy / positive regulation of nitric oxide biosynthetic process / positive regulation of protein catabolic process / disordered domain specific binding / MHC class II protein complex binding
Similarity search - Function
Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / HSP90, C-terminal domain / Histidine kinase-like ATPase, 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. / HSP90, C-terminal domain / Histidine kinase-like ATPase, 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
Chem-T5M / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / OTHER / Resolution: 2.801 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
DepositionJun 21, 2010Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 1, 2010Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3May 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)28,2692
Polymers27,9731
Non-polymers2951
Water1,24369
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)47.231, 41.182, 49.827
Angle α, β, γ (deg.)90.00, 101.28, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 27973.361 Da / Num. of mol.: 1 / Fragment: N-TERMINAL DOMAIN (9-236)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Gene: HSP90, HSP90A, HSP90AA1, HSPC1, HSPCA / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P07900
#2: Chemical ChemComp-T5M / 2-TERT-BUTYL-4-(1,3-DIHYDRO-2H-ISOINDOL-2-YLCARBONYL)PHENOL


Mass: 295.376 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H21NO2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 69 / 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: 1.9 Å3/Da / Density % sol: 34.89 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Wavelength: 1.54178
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 2.8→37.48 Å / Num. obs: 4767 / % possible obs: 96.1 % / Observed criterion σ(I): 0 / Redundancy: 2.4 % / Rmerge(I) obs: 0.15

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Processing

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

Resolution: 2.801→48.8 Å / Cor.coef. Fo:Fc: 0.925 / Cor.coef. Fo:Fc free: 0.784 / SU B: 57.195 / SU ML: 0.604 / Cross valid method: THROUGHOUT / ESU R Free: 0.749 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.40685 223 4.9 %RANDOM
Rwork0.24383 ---
obs0.25166 4356 96.1 %-
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: 42.975 Å2
Baniso -1Baniso -2Baniso -3
1-2.6 Å20 Å2-0.64 Å2
2---4.3 Å20 Å2
3---1.45 Å2
Refinement stepCycle: LAST / Resolution: 2.801→48.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1679 0 22 69 1770
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0221730
X-RAY DIFFRACTIONr_bond_other_d0.0010.021172
X-RAY DIFFRACTIONr_angle_refined_deg1.381.9552337
X-RAY DIFFRACTIONr_angle_other_deg0.9092.9712869
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.4615212
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.13225.280
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.01115317
X-RAY DIFFRACTIONr_dihedral_angle_4_deg27.184157
X-RAY DIFFRACTIONr_chiral_restr0.0720.2264
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0211908
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02334
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: 2.801→2.874 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.234 15 -
Rwork0.326 319 -
obs--97.38 %
Refinement TLS params.Method: refined / Origin x: 11.9108 Å / Origin y: -0.1492 Å / Origin z: 13.0807 Å
111213212223313233
T0.3203 Å2-0.0274 Å2-0.0055 Å2-0.3396 Å2-0.011 Å2--0.2397 Å2
L0.7743 °20.1036 °2-0.0031 °2-3.5502 °2-0.1537 °2--0.8779 °2
S0.0044 Å °-0.0331 Å °-0.0174 Å °0.1639 Å °0.021 Å °0.0939 Å °-0.0894 Å °-0.0055 Å °-0.0254 Å °

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