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- PDB-3wha: Hsp90 alpha N-terminal domain in complex with a tricyclic inhibitor -

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Basic information

Entry
Database: PDB / ID: 3wha
TitleHsp90 alpha N-terminal domain in complex with a tricyclic inhibitor
ComponentsHeat shock protein HSP 90-alpha
KeywordsChaperone/chaperone Inhibitor / Chaperone / Chaperone-chaperone Inhibitor complex
Function / homology
Function and homology information


sperm mitochondrial sheath / sulfonylurea receptor binding / dATP binding / CTP binding / positive regulation of protein polymerization / vRNP Assembly / Scavenging by Class F Receptors / UTP binding / sperm plasma membrane / chaperone-mediated autophagy ...sperm mitochondrial sheath / sulfonylurea receptor binding / dATP binding / CTP binding / positive regulation of protein polymerization / vRNP Assembly / Scavenging by Class F Receptors / 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 / protein insertion into mitochondrial outer membrane / 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 / TPR domain binding / PIWI-interacting RNA (piRNA) biogenesis / Assembly and release of respiratory syncytial virus (RSV) virions / non-chaperonin molecular chaperone ATPase / dendritic growth cone / Sema3A PAK dependent Axon repulsion / protein unfolding / positive regulation of cell size / regulation of protein ubiquitination / HSF1-dependent transactivation / response to unfolded protein / enzyme-substrate adaptor activity / skeletal muscle contraction / regulation of postsynaptic membrane neurotransmitter receptor levels / regulation of protein-containing complex assembly / HSF1 activation / telomere maintenance via telomerase / Attenuation phase / chaperone-mediated protein complex assembly / neurofibrillary tangle assembly / axonal growth cone / RHOBTB2 GTPase cycle / positive regulation of lamellipodium assembly / eNOS activation / nitric oxide metabolic process / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / DNA polymerase binding / positive regulation of defense response to virus by host / response to salt stress / Signaling by ERBB2 / cardiac muscle cell apoptotic process / positive regulation of telomere maintenance via telomerase / 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 / nitric-oxide synthase regulator activity / Recruitment of mitotic centrosome proteins and complexes / Recruitment of NuMA to mitotic centrosomes / activation of innate immune response / Anchoring of the basal body to the plasma membrane / lysosomal lumen / positive regulation of interferon-beta production / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / response to cold / ESR-mediated signaling / Constitutive Signaling by Overexpressed ERBB2 / protein tyrosine kinase binding / AURKA Activation by TPX2 / VEGFR2 mediated vascular permeability / ATP-dependent protein folding chaperone / response to cocaine / Signaling by ERBB2 TMD/JMD mutants / brush border membrane / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / DDX58/IFIH1-mediated induction of interferon-alpha/beta / cellular response to virus / Regulation of actin dynamics for phagocytic cup formation / Regulation of necroptotic cell death / tau protein binding / VEGFA-VEGFR2 Pathway / histone deacetylase binding / positive regulation of protein import into nucleus / Downregulation of ERBB2 signaling / response to estrogen / Chaperone Mediated Autophagy / positive regulation of protein catabolic process / neuron migration / Aggrephagy / disordered domain specific binding / MHC class II protein complex binding / The role of GTSE1 in G2/M progression after G2 checkpoint
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-like ATPase, C-terminal domain / 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 / Heat shock protein Hsp90, N-terminal / Heat shock protein Hsp90 family / Hsp90 protein / Histidine kinase-like ATPase, C-terminal domain / 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 / Histidine kinase/HSP90-like ATPase superfamily / Ribosomal protein S5 domain 2-type fold / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-WHA / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.3 Å
AuthorsFukami, T.A. / Ono, N.
CitationJournal: Bioorg.Med.Chem. / Year: 2014
Title: Design and synthesis of 2-amino-6-(1H,3H-benzo[de]isochromen-6-yl)-1,3,5-triazines as novel Hsp90 inhibitors
Authors: Suda, A. / Kawasaki, K. / Komiyama, S. / Isshiki, Y. / Yoon, D.-O. / Kim, S.-J. / Na, Y.-J. / Hasegawa, K. / Fukami, T.A. / Sato, S. / Miura, T. / Ono, N. / Yamazaki, T. / Saitoh, R. / ...Authors: Suda, A. / Kawasaki, K. / Komiyama, S. / Isshiki, Y. / Yoon, D.-O. / Kim, S.-J. / Na, Y.-J. / Hasegawa, K. / Fukami, T.A. / Sato, S. / Miura, T. / Ono, N. / Yamazaki, T. / Saitoh, R. / Shimma, N. / Shiratori, Y. / Tsukuda, T.
History
DepositionAug 23, 2013Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 29, 2014Provider: repository / Type: Initial release
Revision 1.1Nov 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 / pdbx_struct_conn_angle / struct_conn / 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 / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_symmetry / _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

Downloads & links

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Assembly

Deposited unit
A: Heat shock protein HSP 90-alpha
B: Heat shock protein HSP 90-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,5246
Polymers51,5762
Non-polymers9484
Water11,458636
1
A: Heat shock protein HSP 90-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,2963
Polymers25,7881
Non-polymers5082
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Heat shock protein HSP 90-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,2283
Polymers25,7881
Non-polymers4402
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
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)52,5926
Polymers51,5762
Non-polymers1,0164
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_454-x-1,y,-z-11
Buried area1510 Å2
ΔGint-9 kcal/mol
Surface area19700 Å2
MethodPISA
4
B: Heat shock protein HSP 90-alpha
hetero molecules

B: Heat shock protein HSP 90-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,4566
Polymers51,5762
Non-polymers8804
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_554-x,y,-z-11
Buried area1710 Å2
ΔGint-11 kcal/mol
Surface area19400 Å2
MethodPISA
Unit cell
Length a, b, c (Å)107.170, 98.920, 64.240
Angle α, β, γ (deg.)90.000, 124.550, 90.000
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-302-

MG

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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: 25787.965 Da / Num. of mol.: 2 / Fragment: UNP residues 9-236
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSP90AA1 / Plasmid: pT7-7 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)CP / References: UniProt: P07900
#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical ChemComp-WHA / 4-{[4-amino-6-(5-chloro-1H,3H-benzo[de]isochromen-6-yl)-1,3,5-triazin-2-yl]sulfanyl}butanamide


Mass: 415.897 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H18ClN5O2S
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 636 / 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: 2.7 Å3/Da / Density % sol: 54.5 %
Crystal growTemperature: 278 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 22%(w/v) PEG 3350, 0.2M MgCl2, 0.1M Na-MES, pH 6.5, vapor diffusion, sitting drop, temperature 278K

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: NATIVE
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 22, 2010 / Details: mirrors
RadiationMonochromator: double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.3→44.134 Å / Num. all: 133172 / Num. obs: 133172 / % possible obs: 98.7 % / Redundancy: 3.3 % / Rmerge(I) obs: 0.044 / Rsym value: 0.044 / Net I/σ(I): 14.5
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) allNum. measured allNum. unique all% possible all
1.3-1.333.290.332.2432305981198.64
1.33-1.373.310.292.6232027967799.43
1.37-1.413.250.233.2530455937299.36
1.41-1.453.070.193.9827954911499.49
1.45-1.53.390.164.7629992885499.36
1.5-1.553.370.136.0228851855399.13
1.55-1.613.360.17.3827480817698.97
1.61-1.683.320.098.4626218788698.67
1.68-1.753.140.089.4423603752498.31
1.75-1.843.150.0611.1522723720498.04
1.84-1.943.350.0512.8122746679797.55
1.94-2.063.310.0514.1621356644697.47
2.06-2.23.260.0415.9219770606997.74
2.2-2.373.150.0415.4617752563697.72
2.37-2.62.950.0415.9315490524298.25
2.6-2.913.470.0316.6716405473298.52
2.91-3.363.50.0316.5214797423099.28
3.36-4.113.40.0317.212132357299.1
4.11-5.813.250.0318.998974275798.37
5.81-44.133.660.0314.85561152097.14

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 39.45
Highest resolutionLowest resolution
Rotation2.5 Å28.4 Å
Translation2.5 Å28.4 Å

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Processing

Software
NameVersionClassificationNB
SCALA3.3.16data scaling
PHASER2.1.4phasing
BUSTER-TNTrefinement
PDB_EXTRACT3.11data extraction
XDSdata reduction
BUSTER2.11.2refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3B28

3b28


Resolution: 1.3→44.13 Å / Cor.coef. Fo:Fc: 0.9513 / Cor.coef. Fo:Fc free: 0.9465 / Occupancy max: 1 / Occupancy min: 0.5 / SU R Cruickshank DPI: 0.045 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2003 6705 5.03 %RANDOM
Rwork0.1842 ---
obs0.185 133171 98.64 %-
Displacement parametersBiso max: 71.7 Å2 / Biso mean: 16.8126 Å2 / Biso min: 6.79 Å2
Baniso -1Baniso -2Baniso -3
1--0.8715 Å20 Å2-1.0619 Å2
2--1.602 Å20 Å2
3----0.7305 Å2
Refine analyzeLuzzati coordinate error obs: 0.145 Å
Refinement stepCycle: LAST / Resolution: 1.3→44.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3280 0 63 636 3979
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1255SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes91HARMONIC2
X-RAY DIFFRACTIONt_gen_planes494HARMONIC5
X-RAY DIFFRACTIONt_it3463HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion464SEMIHARMONIC5
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_contact4596SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3463HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg4675HARMONIC21.09
X-RAY DIFFRACTIONt_omega_torsion4.08
X-RAY DIFFRACTIONt_other_torsion13.96
LS refinement shellResolution: 1.3→1.33 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.238 502 5.12 %
Rwork0.2141 9298 -
all0.2153 9800 -
obs--98.64 %

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