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- PDB-3vhc: Hsp90 alpha N-terminal domain in complex with a macrocyclic inhibitor -

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Basic information

Entry
Database: PDB / ID: 3vhc
TitleHsp90 alpha N-terminal domain in complex with a macrocyclic inhibitor
ComponentsHeat shock protein HSP 90-alphaHeat shock response
KeywordsCHAPERONE/CHAPERONE INHIBITOR / chaperone-chaperone inhibitor complex
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 / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / positive regulation of cardiac muscle contraction / positive regulation of defense response to virus by host / Signaling by ERBB2 / Recruitment of mitotic centrosome proteins and complexes / cardiac muscle cell apoptotic process / 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 / positive regulation of interferon-beta production / activation of innate immune response / 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-VHC / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.41 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 1.1Nov 22, 2017Group: Refinement description / Category: software
Revision 1.2Mar 20, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)26,2193
Polymers25,7881
Non-polymers4312
Water5,531307
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)52.795, 44.004, 53.897
Angle α, β, γ (deg.)90.000, 114.350, 90.000
Int Tables number4
Space group name H-MP1211

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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: 25787.965 Da / Num. of mol.: 1 / 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-VHC / 4-amino-20,22-dimethyl-13-oxa-7-thia-3,5,17-triazatetracyclo[17.3.1.1~2,6~.1~8,12~]pentacosa-1(23),2(25),3,5,8(24),9,11,19,21-nonaen-18-one


Mass: 406.501 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H22N4O2S
#3: Chemical ChemComp-MG / MAGNESIUM ION


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


Mass: 18.015 Da / Num. of mol.: 307 / 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: 2.2 Å3/Da / Density % sol: 44 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 33%(w/v) PEG 2000 MME, 0.1M MgCl2, 0.1M Tris-Cl, pH 8.5, 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: May 23, 2006 / 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: 1.41→50 Å / Num. obs: 42294 / % possible obs: 96.9 % / Redundancy: 3.7 % / Rmerge(I) obs: 0.045 / Χ2: 1.111 / Net I/σ(I): 14.3
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
1.41-1.463.50.28839190.456190.7
1.46-1.523.80.21641900.47196.2
1.52-1.593.80.15441930.567197
1.59-1.673.80.11541950.603196.9
1.67-1.783.80.09242320.765197.5
1.78-1.913.80.07142611.008197.6
1.91-2.113.80.05942921.432198.5
2.11-2.413.80.04743291.677199
2.41-3.043.80.0443451.908199.2
3.04-503.60.03343382.111196.6

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Phasing

PhasingMethod: molecular replacement
Phasing MRRfactor: 0.378 / Cor.coef. Fo:Fc: 0.602
Highest resolutionLowest resolution
Rotation3 Å32.46 Å
Translation3 Å32.46 Å

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
MOLREP8.2.01phasing
BUSTER-TNT2.11.2refinement
PDB_EXTRACT3.11data extraction
HKL-2000data reduction
HKL-2000data scaling
BUSTER2.11.2refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.41→14.21 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.9407 / Occupancy max: 1 / Occupancy min: 0.5 / SU R Cruickshank DPI: 0.066 / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.2199 2114 5 %RANDOM
Rwork0.1901 ---
obs0.1915 42262 96.95 %-
Displacement parametersBiso max: 105.82 Å2 / Biso mean: 21.1921 Å2 / Biso min: 8.63 Å2
Baniso -1Baniso -2Baniso -3
1--1.8761 Å20 Å2-2.1414 Å2
2--2.3982 Å20 Å2
3----0.5221 Å2
Refine analyzeLuzzati coordinate error obs: 0.173 Å
Refinement stepCycle: LAST / Resolution: 1.41→14.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1695 0 30 307 2032
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d631SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes52HARMONIC2
X-RAY DIFFRACTIONt_gen_planes251HARMONIC5
X-RAY DIFFRACTIONt_it1782HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion235SEMIHARMONIC5
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_contact2416SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1782HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg2409HARMONIC21.14
X-RAY DIFFRACTIONt_omega_torsion3.97
X-RAY DIFFRACTIONt_other_torsion16.08
LS refinement shellResolution: 1.41→1.45 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.277 166 5.87 %
Rwork0.2457 2661 -
all0.2474 2827 -
obs--96.95 %

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