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- PDB-4eft: Hsp90 Alpha N-terminal Domain in Complex with an Inhibitor 3-Cycl... -

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Basic information

Entry
Database: PDB / ID: 4eft
TitleHsp90 Alpha N-terminal Domain in Complex with an Inhibitor 3-Cyclohexyl-2-(6-hydroxy-1H-indazol-3-yl)-propionitrile
ComponentsHeat shock protein HSP 90-alpha
KeywordsCHAPERONE/CHAPERONE INHIBITOR / ATP BINDING / CHAPERONE-CHAPERONE INHIBITOR complex
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 lamellipodium assembly / axonal growth cone / eNOS activation / DNA polymerase binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / positive regulation of defense response to virus by host / 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 / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / positive regulation of cardiac muscle contraction / activation of innate immune response / nitric-oxide synthase regulator activity / positive regulation of interferon-beta production / response to cold / AURKA Activation by TPX2 / lysosomal lumen / Constitutive Signaling by Overexpressed ERBB2 / ESR-mediated signaling / protein tyrosine kinase binding / 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 / positive regulation of nitric oxide biosynthetic process / Regulation of PLK1 Activity at G2/M Transition / 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-EFT / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.12 Å
AuthorsMusil, D. / Lehmann, M. / Graedler, U. / Buchstaller, H.-P.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Fragment-based discovery of hydroxy-indazole-carboxamides as novel small molecule inhibitors of Hsp90
Authors: Buchstaller, H.-P. / Eggenweiler, H.-M. / Sirrenberg, C. / Graedler, U. / Musil, D. / Hoppe, E. / Zimmermann, A. / Schwartz, H. / Maerz, J. / Bomke, J. / Wegener, A. / Wolf, M.
History
DepositionMar 30, 2012Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jun 27, 2012Provider: repository / Type: Initial release
Revision 1.1Mar 20, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _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)25,9832
Polymers25,7141
Non-polymers2691
Water1,22568
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: Heat shock protein HSP 90-alpha
hetero molecules

A: Heat shock protein HSP 90-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)51,9664
Polymers51,4282
Non-polymers5392
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_765-x+2,-y+1,z1
Buried area1450 Å2
ΔGint-10 kcal/mol
Surface area19220 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.607, 90.339, 99.395
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: 25713.822 Da / Num. of mol.: 1 / Fragment: N-TERMINAL DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSP90A / Production host: Escherichia coli (E. coli) / References: UniProt: P07900
#2: Chemical ChemComp-EFT / (2R)-3-cyclohexyl-2-(6-hydroxy-1H-indazol-3-yl)propanenitrile


Mass: 269.342 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H19N3O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 68 / 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: 2.91 Å3/Da / Density % sol: 57.69 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: Na-Cacodylate, 30% PEG8000, 0.2M Ammonium Sulfate, pH 6.5, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorDetector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.1→33 Å / Num. obs: 16676 / % possible obs: 97.2 % / Observed criterion σ(I): 0 / Biso Wilson estimate: 44.07 Å2

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Processing

Software
NameVersionClassification
MOLREPphasing
BUSTER2.11.1refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.12→20 Å / Cor.coef. Fo:Fc: 0.9449 / Cor.coef. Fo:Fc free: 0.9369 / Occupancy max: 1 / Occupancy min: 1 / SU R Cruickshank DPI: 0.185 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.187 / SU Rfree Blow DPI: 0.158 / SU Rfree Cruickshank DPI: 0.158 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.23 843 5.06 %RANDOM
Rwork0.2063 ---
obs0.2076 16665 95.94 %-
all-16992 --
Displacement parametersBiso max: 128.35 Å2 / Biso mean: 55.21 Å2 / Biso min: 28.13 Å2
Baniso -1Baniso -2Baniso -3
1--1.2276 Å20 Å20 Å2
2--5.9191 Å20 Å2
3----4.6915 Å2
Refine analyzeLuzzati coordinate error obs: 0.373 Å
Refinement stepCycle: LAST / Resolution: 2.12→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1626 0 20 68 1714
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d597SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes46HARMONIC2
X-RAY DIFFRACTIONt_gen_planes237HARMONIC5
X-RAY DIFFRACTIONt_it1675HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion230SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact1882SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1675HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg2260HARMONIC21.1
X-RAY DIFFRACTIONt_omega_torsion3.19
X-RAY DIFFRACTIONt_other_torsion16.5
LS refinement shellResolution: 2.12→2.27 Å / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.4048 140 5.16 %
Rwork0.3932 2574 -
all0.3937 2714 -
obs--95.94 %
Refinement TLS params.Method: refined / Origin x: 66.5983 Å / Origin y: 30.5117 Å / Origin z: 29.3148 Å
111213212223313233
T-0.1679 Å20.0059 Å2-0.0412 Å2-0.0525 Å2-0.0186 Å2---0.158 Å2
L4.5092 °2-0.07 °2-0.3982 °2-1.8372 °20.5383 °2--2.8441 °2
S0.0136 Å °-0.0069 Å °0.2222 Å °-0.1142 Å °-0.0182 Å °0.0728 Å °-0.0857 Å °0.0799 Å °0.0046 Å °
Refinement TLS groupSelection details: { A|17 - A|223 }

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