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

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Basic information

Entry
Database: PDB / ID: 4lwf
TitleCrystal Structure of the human Hsp90-alpha N-domain bound to the hsp90 inhibitor FJ3
ComponentsHeat shock protein HSP 90-alpha
KeywordsCHAPERONE / Rossmann Fold / ATP Binding / molecularchaperone
Function / homology
Function and homology information


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 / 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 / protein insertion into mitochondrial outer membrane / chaperone-mediated autophagy / telomerase holoenzyme complex assembly / Respiratory syncytial virus genome replication / 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 / Assembly and release of respiratory syncytial virus (RSV) virions / dendritic growth cone / regulation of postsynaptic membrane neurotransmitter receptor levels / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / skeletal muscle contraction / telomere maintenance via telomerase / protein unfolding / HSF1-dependent transactivation / response to unfolded protein / positive regulation of cell size / chaperone-mediated protein complex assembly / regulation of protein-containing complex assembly / HSF1 activation / Attenuation phase / RHOBTB2 GTPase cycle / positive regulation of defense response to virus by host / eNOS activation / positive regulation of lamellipodium assembly / axonal growth cone / DNA polymerase binding / activation of innate immune response / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / Signaling by ERBB2 / response to salt stress / cardiac muscle cell apoptotic process / endocytic vesicle lumen / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / positive regulation of cardiac muscle contraction / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / nitric-oxide synthase regulator activity / positive regulation of interferon-beta production / response to cold / protein tyrosine kinase binding / AURKA Activation by TPX2 / Constitutive Signaling by Overexpressed ERBB2 / lysosomal lumen / ESR-mediated signaling / VEGFR2 mediated vascular permeability / response to cocaine / ATP-dependent protein folding chaperone / Signaling by ERBB2 TMD/JMD mutants / brush border membrane / neuron migration / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / DDX58/IFIH1-mediated induction of interferon-alpha/beta / Signaling by ERBB2 KD Mutants / tau protein binding / Regulation of necroptotic cell death / cellular response to virus / Regulation of actin dynamics for phagocytic cup formation / Downregulation of ERBB2 signaling / VEGFA-VEGFR2 Pathway / histone deacetylase binding / positive regulation of protein import into nucleus / Aggrephagy / Chaperone Mediated Autophagy / response to estrogen / positive regulation of protein catabolic process / The role of GTSE1 in G2/M progression after G2 checkpoint / disordered domain specific binding / Regulation of PLK1 Activity at G2/M Transition / positive regulation of nitric oxide biosynthetic process / 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 ATPase, C-terminal domain / Heat Shock Protein 90 / 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 / 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 ATPase, C-terminal domain / Heat Shock Protein 90 / 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-FJ3 / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 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)23,4982
Polymers23,2631
Non-polymers2341
Water1,49583
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.463, 88.709, 99.752
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: 23263.402 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 17-224
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-FJ3 / 4-(5-amino-1,2-oxazol-3-yl)-6-(propan-2-yl)benzene-1,3-diol


Mass: 234.251 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H14N2O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 83 / 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: 3.11 Å3/Da / Density % sol: 60.48 %
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: Si 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 1.75→34.459 Å / Num. obs: 29590 / % possible obs: 99.8 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 7.2 % / Rmerge(I) obs: 0.061 / Rsym value: 0.061 / Net I/σ(I): 48.65

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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: 1.75→34.459 Å / SU ML: 0.17 / σ(F): 0 / Phase error: 19.95 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2088 1956 6.81 %
Rwork0.1864 --
obs0.1879 28720 96.77 %
Solvent computationShrinkage radii: 1.17 Å / VDW probe radii: 1.4 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 44.147 Å2 / ksol: 0.386 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--3.1847 Å20 Å2-0 Å2
2--4.289 Å20 Å2
3----1.1043 Å2
Refinement stepCycle: LAST / Resolution: 1.75→34.459 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1626 0 17 83 1726
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0061677
X-RAY DIFFRACTIONf_angle_d1.0282265
X-RAY DIFFRACTIONf_dihedral_angle_d14.654625
X-RAY DIFFRACTIONf_chiral_restr0.073258
X-RAY DIFFRACTIONf_plane_restr0.004288
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 (%)
1.7498-1.81240.28131720.2251237886
1.8124-1.88490.24191850.1917250893
1.8849-1.97070.22351960.1748260796
1.9707-2.07460.2071940.1818266998
2.0746-2.20450.21121970.1755269899
2.2045-2.37470.23071980.1893271999
2.3747-2.61360.22432010.2076275399
2.6136-2.99160.25962010.21612764100
2.9916-3.76840.2142030.19222792100
3.7684-34.46580.16422090.1641287698
Refinement TLS params.Method: refined / Origin x: -0.669 Å / Origin y: -14.4079 Å / Origin z: -20.4862 Å
111213212223313233
T0.1718 Å2-0.0059 Å2-0.0146 Å2-0.1636 Å2-0.0196 Å2--0.1671 Å2
L2.0023 °2-0.2598 °2-0.1141 °2-0.9187 °20.1312 °2--1.0992 °2
S0.0227 Å °-0.1804 Å °0.0473 Å °-0.0035 Å °-0.0042 Å °0.0268 Å °-0.0504 Å °0.07 Å °-0.0193 Å °
Refinement TLS groupSelection details: ALL

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