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- PDB-4lwh: Crystal Structure of the human Hsp90-alpha N-domain bound to the ... -

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Basic information

Entry
Database: PDB / ID: 4lwh
TitleCrystal Structure of the human Hsp90-alpha N-domain bound to the hsp90 inhibitor FJ5
ComponentsHeat shock protein HSP 90-alpha
KeywordsCHAPERONE / Rossmann Fold / ATP Binding / molecularchaperone
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 / 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 / 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-FJ5 / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsLi, J. / Shi, F. / Xiong, B. / He, J.
CitationJournal: Eur.J.Med.Chem. / Year: 2014
Title: Discovery of potent N-(isoxazol-5-yl)amides as HSP90 inhibitors.
Authors: Chen, D. / Shen, A. / Li, J. / Shi, F. / Chen, W. / Ren, J. / Liu, H. / Xu, Y. / Wang, X. / Yang, X. / Sun, Y. / Yang, M. / He, J. / Wang, Y. / Zhang, L. / Huang, M. / Geng, M. / Xiong, B. / Shen, J.
History
DepositionJul 27, 2013Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jul 30, 2014Provider: repository / Type: Initial release
Revision 1.1Oct 12, 2016Group: Database references
Revision 1.2Nov 8, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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)23,8702
Polymers23,3931
Non-polymers4781
Water2,126118
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)66.417, 89.334, 99.813
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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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: 23392.516 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 16-224
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-FJ5 / N-{3-[2,4-dihydroxy-5-(propan-2-yl)phenyl]-4-[4-(morpholin-4-ylmethyl)phenyl]-1,2-oxazol-5-yl}cyclopropanecarboxamide


Mass: 477.552 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H31N3O5
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 118 / 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: 3.16 Å3/Da / Density % sol: 61.13 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 20-25% (w/v) PEG 2000 monomethyl ether, 200mM magnesium chloride, 100mM sodium cacodylate pH 6.5,, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U
DetectorType: ADSC QUANTUM 315r / Detector: CCD
RadiationMonochromator: 0.97913 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 1.7→33.283 Å / Num. obs: 33011 / % possible obs: 99.7 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 7.2 % / Rmerge(I) obs: 0.055 / Rsym value: 0.055 / Net I/σ(I): 37.549

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Processing

Software
NameVersionClassification
HKL-2000data collection
PHENIXmodel building
PHENIX(phenix.refine: 1.6.2_432)refinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3T0Z

3t0z


Resolution: 1.7→33.283 Å / SU ML: 0.15 / σ(F): 0 / Phase error: 19.45 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.204 1965 6.1 %
Rwork0.1931 --
obs0.1938 32199 97.57 %
Solvent computationShrinkage radii: 1.17 Å / VDW probe radii: 1.4 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 40.127 Å2 / ksol: 0.39 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--1.8112 Å2-0 Å20 Å2
2--2.4324 Å20 Å2
3----0.6212 Å2
Refinement stepCycle: LAST / Resolution: 1.7→33.283 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1635 0 35 118 1788
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0061700
X-RAY DIFFRACTIONf_angle_d1.0642296
X-RAY DIFFRACTIONf_dihedral_angle_d17.577642
X-RAY DIFFRACTIONf_chiral_restr0.075258
X-RAY DIFFRACTIONf_plane_restr0.006290
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 10

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.7003-1.7610.2411860.2212280392
1.761-1.83160.26971830.2116289094
1.8316-1.91490.22581940.1875295096
1.9149-2.01580.20571980.1861301398
2.0158-2.14210.21211980.1874305599
2.1421-2.30750.22191970.1923304599
2.3075-2.53960.21321990.2028306199
2.5396-2.90690.21022020.21213107100
2.9069-3.66170.20672010.20263124100
3.6617-33.28950.17642070.1739318697

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