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- PDB-4cwn: Human HSP90 alpha N-terminal domain in complex with an Aminotriaz... -

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Basic information

Entry
Database: PDB / ID: 4cwn
TitleHuman HSP90 alpha N-terminal domain in complex with an Aminotriazoloquinazoline inhibitor
ComponentsHEAT SHOCK PROTEIN HSP 90-ALPHAHeat shock response
KeywordsCHAPERONE
Function / homology
Function and homology information


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 / positive regulation of tau-protein kinase activity / protein insertion into mitochondrial outer membrane / telomerase holoenzyme complex assembly / chaperone-mediated autophagy / 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 / regulation of postsynaptic membrane neurotransmitter receptor levels / dendritic growth cone / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / positive regulation of cell size / skeletal muscle contraction / protein unfolding / regulation of protein-containing complex assembly / HSF1-dependent transactivation / telomere maintenance via telomerase / response to unfolded protein / HSF1 activation / chaperone-mediated protein complex assembly / Attenuation phase / RHOBTB2 GTPase cycle / DNA polymerase binding / positive regulation of lamellipodium assembly / axonal growth cone / eNOS activation / endocytic vesicle lumen / 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 / positive regulation of cardiac muscle contraction / cardiac muscle cell apoptotic process / Signaling by ERBB2 / Recruitment of mitotic centrosome proteins and complexes / response to salt stress / positive regulation of telomerase activity / Recruitment of NuMA to mitotic centrosomes / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / protein tyrosine kinase binding / Anchoring of the basal body to the plasma membrane / activation of innate immune response / positive regulation of interferon-beta production / response to cold / nitric-oxide synthase regulator activity / lysosomal lumen / Constitutive Signaling by Overexpressed ERBB2 / ESR-mediated signaling / AURKA Activation by TPX2 / response to cocaine / VEGFR2 mediated vascular permeability / brush border membrane / ATP-dependent protein folding chaperone / Signaling by ERBB2 TMD/JMD mutants / neuron migration / tau protein binding / DDX58/IFIH1-mediated induction of interferon-alpha/beta / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / Regulation of necroptotic cell death / Regulation of actin dynamics for phagocytic cup formation / Downregulation of ERBB2 signaling / cellular response to virus / VEGFA-VEGFR2 Pathway / Aggrephagy / Chaperone Mediated Autophagy / positive regulation of protein import into nucleus / response to estrogen / histone deacetylase binding / positive regulation of protein catabolic process / The role of GTSE1 in G2/M progression after G2 checkpoint / positive regulation of nitric oxide biosynthetic process / regulation of protein localization / disordered domain specific binding / Regulation of PLK1 Activity at G2/M Transition / melanosome / unfolded protein binding
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-6LV / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / OTHER / Resolution: 1.8 Å
AuthorsCasale, E. / Amboldi, N. / Brasca, G. / Caronni, D. / Colombo, N. / Dalvit, C. / Felder, E.R. / Fogliatto, G. / Isacchi, A. / Mantegani, S. ...Casale, E. / Amboldi, N. / Brasca, G. / Caronni, D. / Colombo, N. / Dalvit, C. / Felder, E.R. / Fogliatto, G. / Isacchi, A. / Mantegani, S. / Polucci, P. / Riceputi, L. / Sola, F. / Visco, C. / Zuccotto, F. / Casuscelli, F.
CitationJournal: Bioorg.Med.Chem. / Year: 2014
Title: Fragment-Based Hit Discovery and Structure-Based Optimization of Aminotriazoloquinazolines as Novel Hsp90 Inhibitors.
Authors: Casale, E. / Amboldi, N. / Brasca, M.G. / Caronni, D. / Colombo, N. / Dalvit, C. / Felder, E.R. / Fogliatto, G. / Galvani, A. / Isacchi, A. / Polucci, P. / Riceputi, L. / Sola, F. / Visco, C. ...Authors: Casale, E. / Amboldi, N. / Brasca, M.G. / Caronni, D. / Colombo, N. / Dalvit, C. / Felder, E.R. / Fogliatto, G. / Galvani, A. / Isacchi, A. / Polucci, P. / Riceputi, L. / Sola, F. / Visco, C. / Zuccotto, F. / Casuscelli, F.
History
DepositionApr 3, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 9, 2014Provider: repository / Type: Initial release
Revision 1.1Aug 6, 2014Group: Database references
Revision 1.2Jun 28, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type

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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)26,1462
Polymers25,8111
Non-polymers3351
Water3,477193
1
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)52,2934
Polymers51,6222
Non-polymers6712
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,-y,z1
Buried area1530 Å2
ΔGint-8.8 kcal/mol
Surface area19480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)67.179, 90.712, 99.232
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 response / 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-6LV / 5-(3,5-dimethoxybenzyl)[1,2,4]triazolo[1,5-c]quinazolin-2-amine


Mass: 335.360 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H17N5O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 193 / 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: 2.93 Å3/Da / Density % sol: 57.6 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.5418
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Oct 3, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.8→30 Å / Num. obs: 28100 / % possible obs: 98.6 % / Observed criterion σ(I): 0 / Redundancy: 6.6 % / Rmerge(I) obs: 0.07 / Net I/σ(I): 19
Reflection shellResolution: 1.8→1.86 Å / Rmerge(I) obs: 0.32 / Mean I/σ(I) obs: 6.4 / % possible all: 95.9

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Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 1.8→30 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.931 / SU B: 2.043 / SU ML: 0.066 / Cross valid method: THROUGHOUT / ESU R: 0.113 / ESU R Free: 0.11 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.22832 1416 5 %RANDOM
Rwork0.19811 ---
obs0.19961 26676 98.57 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.163 Å2
Baniso -1Baniso -2Baniso -3
1--0.45 Å20 Å20 Å2
2--0.43 Å20 Å2
3---0.02 Å2
Refinement stepCycle: LAST / Resolution: 1.8→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1626 0 25 193 1844
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.021680
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.2621.982268
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4975206
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.01525.13574
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.25115306
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.287157
X-RAY DIFFRACTIONr_chiral_restr0.0840.2257
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021239
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: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.377 87 -
Rwork0.413 1780 -
obs--94.92 %

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