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- PDB-4b7p: Structure of HSP90 with NMS-E973 inhibitor bound -

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Basic information

Entry
Database: PDB / ID: 4b7p
TitleStructure of HSP90 with NMS-E973 inhibitor bound
ComponentsHEAT SHOCK PROTEIN HSP 90-ALPHA
KeywordsCHAPERONE / ATPASE / ATP-BINDING
Function / homology
Function and homology information


sperm mitochondrial sheath / sulfonylurea receptor binding / CTP binding / positive regulation of protein polymerization / Scavenging by Class F Receptors / vRNP Assembly / UTP binding / dATP binding / sperm plasma membrane / chaperone-mediated autophagy ...sperm mitochondrial sheath / sulfonylurea receptor binding / CTP binding / positive regulation of protein polymerization / Scavenging by Class F Receptors / vRNP Assembly / UTP binding / dATP binding / sperm plasma membrane / chaperone-mediated autophagy / Rho GDP-dissociation inhibitor binding / mitochondrial transport / Respiratory syncytial virus genome replication / telomerase holoenzyme complex assembly / 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 / Uptake and function of diphtheria toxin / protein import into mitochondrial matrix / dendritic growth cone / TPR domain binding / PIWI-interacting RNA (piRNA) biogenesis / non-chaperonin molecular chaperone ATPase / Assembly and release of respiratory syncytial virus (RSV) virions / protein unfolding / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / positive regulation of cell size / HSF1-dependent transactivation / protein folding chaperone complex / response to unfolded protein / regulation of protein-containing complex assembly / enzyme-substrate adaptor activity / Attenuation phase / HSF1 activation / neurofibrillary tangle assembly / chaperone-mediated protein complex assembly / RHOBTB2 GTPase cycle / axonal growth cone / telomere maintenance via telomerase / regulation of postsynaptic membrane neurotransmitter receptor levels / positive regulation of lamellipodium assembly / nitric oxide metabolic process / skeletal muscle contraction / positive regulation of defense response to virus by host / eNOS activation / Signaling by ERBB2 / response to salt stress / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / cardiac muscle cell apoptotic process / positive regulation of telomere maintenance via telomerase / DNA polymerase binding / 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 / Recruitment of NuMA to mitotic centrosomes / lysosomal lumen / Anchoring of the basal body to the plasma membrane / ESR-mediated signaling / positive regulation of interferon-beta production / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / Constitutive Signaling by Overexpressed ERBB2 / response to cold / protein tyrosine kinase binding / 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 / cellular response to virus / Signaling by ERBB2 KD Mutants / Regulation of actin dynamics for phagocytic cup formation / positive regulation of protein import into nucleus / DDX58/IFIH1-mediated induction of interferon-alpha/beta / response to estrogen / VEGFA-VEGFR2 Pathway / Regulation of necroptotic cell death / tau protein binding / Downregulation of ERBB2 signaling / neuron migration / histone deacetylase binding / Chaperone Mediated Autophagy / positive regulation of nitric oxide biosynthetic process / disordered domain specific binding / Aggrephagy / 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 / Heat Shock Protein 90 / 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-, 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 / Heat Shock Protein 90 / 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-, 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 / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-9UN / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsFogliatto, G. / Gianellini, L. / Brasca, M.G. / Casale, E. / Ballinari, D. / Ciomei, M. / Degrassi, A. / De Ponti, A. / Germani, M. / Guanci, M. ...Fogliatto, G. / Gianellini, L. / Brasca, M.G. / Casale, E. / Ballinari, D. / Ciomei, M. / Degrassi, A. / De Ponti, A. / Germani, M. / Guanci, M. / Paolucci, M. / Polucci, P. / Russo, M. / Sola, F. / Valsasina, B. / Visco, C. / Zuccotto, F. / Donati, D. / Felder, E. / Galvani, A. / Pesenti, E. / Mantegani, S. / Isacchi, A.
CitationJournal: Clin.Cancer Res. / Year: 2013
Title: Nms-E973, a Novel Synthetic Inhibitor of Hsp90 with Activity in Models of Drug Resistance to Targeted Agents, Including Intracranial Metastases.
Authors: Fogliatto, G. / Gianellini, L.M. / Brasca, M.G. / Casale, E. / Ballinari, D. / Ciomei, M. / Degrassi, A. / De Ponti, A. / Germani, M. / Guanci, M. / Paolucci, M. / Polucci, P. / Russo, M. / ...Authors: Fogliatto, G. / Gianellini, L.M. / Brasca, M.G. / Casale, E. / Ballinari, D. / Ciomei, M. / Degrassi, A. / De Ponti, A. / Germani, M. / Guanci, M. / Paolucci, M. / Polucci, P. / Russo, M. / Sola, F. / Valsasina, B. / Visco, C. / Zuccotto, F. / Donati, D. / Felder, E. / Pesenti, E. / Mantegani, S. / Galvani, A. / Isacchi, A.
History
DepositionAug 21, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 29, 2013Provider: repository / Type: Initial release
Revision 1.1Jul 17, 2013Group: Database references
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)26,2652
Polymers25,8111
Non-polymers4541
Water2,882160
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)52.746, 44.042, 53.621
Angle α, β, γ (deg.)90.00, 115.59, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 25810.936 Da / Num. of mol.: 1 / Fragment: N-TERMINAL DOMAIN, RESIDUES 9-236
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21 / References: UniProt: P07900
#2: Chemical ChemComp-9UN / 5-[2,4-dihydroxy-6-(4-nitrophenoxy)phenyl]-N-(1-methylpiperidin-4-yl)-1,2-oxazole-3-carboxamide


Mass: 454.433 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H22N4O7
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 160 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsTHE FIRST TWO RESIDUES GP ARE EXPRESSION TAG

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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: 2.18 Å3/Da / Density % sol: 43.48 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.87
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Feb 12, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.87 Å / Relative weight: 1
ReflectionResolution: 1.7→30 Å / Num. obs: 24199 / % possible obs: 98.3 % / Observed criterion σ(I): 2 / Redundancy: 4 % / Rmerge(I) obs: 0.04 / Net I/σ(I): 17
Reflection shellResolution: 1.7→1.8 Å / Rmerge(I) obs: 0.2 / % possible all: 96.9

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→30.34 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.946 / SU B: 1.701 / SU ML: 0.058 / Cross valid method: THROUGHOUT / ESU R: 0.106 / ESU R Free: 0.098 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1972 1228 5.1 %RANDOM
Rwork0.17426 ---
obs0.17549 22969 98.28 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Refinement stepCycle: LAST / Resolution: 1.7→30.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1688 0 33 160 1881
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.021750
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.8661.9862360
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.5965213
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.96525.44379
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.81815323
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.757157
X-RAY DIFFRACTIONr_chiral_restr0.1270.2266
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.021297
X-RAY DIFFRACTIONr_gen_planes_other
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: 1.7→1.744 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.278 93 -
Rwork0.206 1564 -
obs--97.13 %

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