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- PDB-4xiq: Discovery of novel oxazepine and diazepine carboxamides as two ne... -

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Basic information

Entry
Database: PDB / ID: 4xiq
TitleDiscovery of novel oxazepine and diazepine carboxamides as two new classes of heat shock protein 90 inhibitors
ComponentsHeat shock protein HSP 90-alpha
KeywordsChaperone/chaperone Inhibitor / 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 / activation of innate immune response / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / lysosomal lumen / positive regulation of interferon-beta production / response to cold / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / 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-40Y / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.84 Å
AuthorsNeubert, T. / Zuccola, H.J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2015
Title: Discovery of novel oxazepine and diazepine carboxamides as two new classes of heat shock protein 90 inhibitors.
Authors: Neubert, T. / Numa, M. / Ernst, J. / Clemens, J. / Krenitsky, P. / Liu, M. / Fleck, B. / Woody, L. / Zuccola, H. / Stamos, D.
History
DepositionJan 7, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 4, 2015Provider: repository / Type: Initial release
Revision 1.1Apr 1, 2015Group: Database references
Revision 1.2Jun 1, 2016Group: Data collection
Revision 1.3Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,7064
Polymers26,1831
Non-polymers5233
Water2,918162
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)53,4128
Polymers52,3672
Non-polymers1,0456
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,-y,z1
Buried area2930 Å2
ΔGint-17 kcal/mol
Surface area19180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.837, 90.977, 99.056
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 / HSP86 / Lipopolysaccharide-associated protein 2 / LPS-associated protein 2 / ...Heat shock 86 kDa / HSP86 / Lipopolysaccharide-associated protein 2 / LPS-associated protein 2 / Renal carcinoma antigen NY-REN-38


Mass: 26183.400 Da / Num. of mol.: 1 / Fragment: residues 131-358
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSP90AA1, HSP90A, HSPC1, HSPCA / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P07900
#2: Chemical ChemComp-40Y / 8,11,11-trimethyl-9-oxo-6,7,9,10,11,12-hexahydroindolo[2,1-d][1,5]benzoxazepine-3-carboxamide


Mass: 338.400 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H22N2O3
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 162 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.88 Å3/Da / Density % sol: 57.22 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 20-25% PEGMME2K, 100MM MGCL2, 100MM CACODYLATE PH 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.9774 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 10, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9774 Å / Relative weight: 1
ReflectionResolution: 1.84→55.404 Å / Num. obs: 23149 / % possible obs: 86.4 % / Redundancy: 5.2 % / Biso Wilson estimate: 22.68 Å2 / Net I/σ(I): 13.5

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
PROCESSdata reduction
PROCESSdata scaling
BUSTERphasing
RefinementResolution: 1.84→55.4 Å / Cor.coef. Fo:Fc: 0.9412 / Cor.coef. Fo:Fc free: 0.9371 / SU R Cruickshank DPI: 0.129 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.134 / SU Rfree Blow DPI: 0.116 / SU Rfree Cruickshank DPI: 0.113
RfactorNum. reflection% reflectionSelection details
Rfree0.2058 1228 5.35 %RANDOM
Rwork0.1924 ---
obs0.1931 22963 86.37 %-
Displacement parametersBiso mean: 24.91 Å2
Baniso -1Baniso -2Baniso -3
1-2.633 Å20 Å20 Å2
2---2.7195 Å20 Å2
3---0.0865 Å2
Refinement stepCycle: 1 / Resolution: 1.84→55.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1667 0 37 162 1866
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0131734HARMONIC1
X-RAY DIFFRACTIONt_angle_deg1.372344HARMONIC1
X-RAY DIFFRACTIONt_dihedral_angle_d630SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes46HARMONIC2
X-RAY DIFFRACTIONt_gen_planes265HARMONIC5
X-RAY DIFFRACTIONt_it1734HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.2
X-RAY DIFFRACTIONt_other_torsion14.87
X-RAY DIFFRACTIONt_improper_torsion
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_contact2172SEMIHARMONIC4
LS refinement shellResolution: 1.84→1.92 Å / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.1944 130 4.5 %
Rwork0.2083 2761 -
all0.2077 2891 -
obs--86.37 %

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