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- PDB-3vhd: Hsp90 alpha N-terminal domain in complex with a macrocyclic inhib... -

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Basic information

Entry
Database: PDB / ID: 3vhd
TitleHsp90 alpha N-terminal domain in complex with a macrocyclic inhibitor, CH5164840
ComponentsHeat shock protein HSP 90-alpha
KeywordsCHAPERONE/CHAPERONE INHIBITOR / chaperone-chaperone inhibitor complex
Function / homology
Function and homology information


sperm plasma membrane / sperm mitochondrial sheath / sulfonylurea receptor binding / CTP binding / Scavenging by Class F Receptors / positive regulation of protein polymerization / vRNP Assembly / UTP binding / dATP binding / telomerase holoenzyme complex assembly ...sperm plasma membrane / sperm mitochondrial sheath / sulfonylurea receptor binding / CTP binding / Scavenging by Class F Receptors / positive regulation of protein polymerization / vRNP Assembly / UTP binding / dATP binding / telomerase holoenzyme complex assembly / chaperone-mediated autophagy / mitochondrial transport / Respiratory syncytial virus genome replication / Rho GDP-dissociation inhibitor binding / 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 / Uptake and function of diphtheria toxin / dendritic growth cone / protein import into mitochondrial matrix / TPR domain binding / PIWI-interacting RNA (piRNA) biogenesis / non-chaperonin molecular chaperone ATPase / Assembly and release of respiratory syncytial virus (RSV) virions / positive regulation of cell size / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / protein folding chaperone complex / HSF1-dependent transactivation / response to unfolded protein / regulation of protein-containing complex assembly / protein unfolding / Attenuation phase / enzyme-substrate adaptor activity / HSF1 activation / chaperone-mediated protein complex assembly / neurofibrillary tangle assembly / axonal growth cone / telomere maintenance via telomerase / RHOBTB2 GTPase cycle / positive regulation of lamellipodium assembly / regulation of postsynaptic membrane neurotransmitter receptor levels / nitric oxide metabolic process / response to cold / positive regulation of defense response to virus by host / response to salt stress / skeletal muscle contraction / Signaling by ERBB2 / eNOS activation / cardiac muscle cell apoptotic process / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / positive regulation of telomere maintenance via telomerase / endocytic vesicle lumen / DNA polymerase binding / 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 / Recruitment of NuMA to mitotic centrosomes / lysosomal lumen / Anchoring of the basal body to the plasma membrane / ESR-mediated signaling / activation of innate immune response / positive regulation of interferon-beta production / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / protein tyrosine kinase binding / AURKA Activation by TPX2 / Constitutive Signaling by Overexpressed ERBB2 / nitric-oxide synthase regulator activity / ATP-dependent protein folding chaperone / VEGFR2 mediated vascular permeability / response to cocaine / brush border membrane / myelin sheath / Signaling by ERBB2 TMD/JMD mutants / neuron migration / cellular response to virus / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / positive regulation of protein import into nucleus / Signaling by ERBB2 KD Mutants / protein refolding / Regulation of actin dynamics for phagocytic cup formation / DDX58/IFIH1-mediated induction of interferon-alpha/beta / response to estrogen / VEGFA-VEGFR2 Pathway / Regulation of necroptotic cell death / tau protein binding / histone deacetylase binding / positive regulation of nitric oxide biosynthetic process / Downregulation of ERBB2 signaling / Chaperone Mediated Autophagy / disordered domain specific binding
Similarity search - Function
Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / Histidine kinase-like ATPase, C-terminal domain / Heat Shock Protein 90 / 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-, DNA gyrase B-, and HSP90-like ATPase ...Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / Histidine kinase-like ATPase, C-terminal domain / Heat Shock Protein 90 / 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-, 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-VHE / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.52 Å
AuthorsFukami, T.A. / Ono, N.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Design and synthesis of novel macrocyclic 2-amino-6-arylpyrimidine Hsp90 inhibitors
Authors: Suda, A. / Koyano, H. / Hayase, T. / Hada, K. / Kawasaki, K. / Komiyama, S. / Hasegawa, K. / Fukami, T.A. / Sato, S. / Miura, T. / Ono, N. / Yamazaki, T. / Saitoh, R. / Shimma, N. / Shiratori, Y. / Tsukuda, T.
History
DepositionAug 24, 2011Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 18, 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

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)52,3474
Polymers51,5762
Non-polymers7712
Water11,169620
1
A: Heat shock protein HSP 90-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,1732
Polymers25,7881
Non-polymers3851
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Heat shock protein HSP 90-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,1732
Polymers25,7881
Non-polymers3851
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)40.995, 53.061, 54.178
Angle α, β, γ (deg.)114.600, 91.120, 90.170
Int Tables number1
Space group name H-MP1

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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: N-terminal domain
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-VHE / 4-amino-18,20-dimethyl-7-thia-3,5,11,15-tetraazatricyclo[15.3.1.1(2,6)]docosa-1(20),2,4,6(22),17(21),18-hexaene-10,16-dione


Mass: 385.483 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H23N5O2S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 620 / 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: 2.1 Å3/Da / Density % sol: 40.4 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 31%(w/v) PEG 5000 MME, 0.2M MgCl2, 5%(v/v) Glycerol, 0.1M Na-MES, pH 6.5, vapor diffusion, hanging drop, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: AR-NW12A / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Feb 27, 2007 / 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: 1.52→45.129 Å / Num. all: 59489 / Num. obs: 59489 / % possible obs: 93.2 % / Redundancy: 2 % / Rmerge(I) obs: 0.071 / Rsym value: 0.071 / Net I/σ(I): 9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) allRmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRrim(I) allRsym valueNet I/σ(I) obs% possible all
1.52-1.561.90.5310.3491.9579630080.3760.5310.349263.5
1.56-1.61.90.4320.252.7746339030.3060.4320.252.585.3
1.6-1.6520.4040.2223836642310.2860.4040.2222.894.8
1.65-1.720.3620.2053.3811741070.2560.3620.2053.194.7
1.7-1.7620.2830.1634.1797440320.20.2830.1633.995.2
1.76-1.8220.2290.1365.1765938740.1620.2290.1364.895.5
1.82-1.8920.1780.1086.5746837850.1260.1780.1086.195.6
1.89-1.9620.1480.0917.8724436630.1050.1480.0917.496.3
1.96-2.0520.1130.06910690734920.080.1130.0699.196.3
2.05-2.1520.0980.0689.7665933720.070.0980.06810.296.8
2.15-2.2720.0810.06510.8623731620.0570.0810.06511.796.5
2.27-2.420.0720.05711.8601130440.0510.0720.05712.797
2.4-2.5720.0650.05212.6564228640.0460.0650.05213.997.4
2.57-2.7820.0580.04813.6522126500.0410.0580.0481597.6
2.78-3.0420.0520.04513.9483624600.0360.0520.04516.498
3.04-3.420.0490.04215.6440822410.0350.0490.0421898.2
3.4-3.9220.0480.03816.4385119740.0340.0480.03819.198.5
3.92-4.811.90.0490.04115322116620.0350.0490.04120.298.3
4.81-6.81.90.0580.03918.2245212800.0410.0580.0391998.2
6.8-45.1291.80.0670.05112.312576850.0470.0670.05119.896.3

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation1.7 Å40.98 Å
Translation1.7 Å40.98 Å

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Processing

Software
NameVersionClassificationNB
MOSFLM6.2.6data reduction
SCALA3.2.25data scaling
MOLREP9.4.09phasing
BUSTER-TNT2.11.2refinement
PDB_EXTRACT3.11data extraction
BUSTER2.11.2refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.52→40.98 Å / Cor.coef. Fo:Fc: 0.9602 / Cor.coef. Fo:Fc free: 0.9481 / Occupancy max: 1 / Occupancy min: 0.5 / SU R Cruickshank DPI: 0.078 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.1964 3016 5.07 %RANDOM
Rwork0.1639 ---
obs0.1656 59487 93.18 %-
Displacement parametersBiso max: 90.88 Å2 / Biso mean: 19.9259 Å2 / Biso min: 5.42 Å2
Baniso -1Baniso -2Baniso -3
1-1.6076 Å20.0748 Å2-0.1952 Å2
2---0.2805 Å2-0.0919 Å2
3----1.3271 Å2
Refine analyzeLuzzati coordinate error obs: 0.149 Å
Refinement stepCycle: LAST / Resolution: 1.52→40.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3371 0 54 620 4045
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1243SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes117HARMONIC2
X-RAY DIFFRACTIONt_gen_planes497HARMONIC5
X-RAY DIFFRACTIONt_it3489HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion471SEMIHARMONIC5
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_contact4633SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3489HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg4704HARMONIC21.09
X-RAY DIFFRACTIONt_omega_torsion3.9
X-RAY DIFFRACTIONt_other_torsion14.87
LS refinement shellResolution: 1.52→1.56 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2567 148 4.93 %
Rwork0.203 2855 -
all0.2057 3003 -
obs--93.18 %

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