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- PDB-3r92: Discovery of a macrocyclic o-aminobenzamide Hsp90 inhibitor with ... -

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Basic information

Entry
Database: PDB / ID: 3r92
TitleDiscovery of a macrocyclic o-aminobenzamide Hsp90 inhibitor with heterocyclic tether that shows extended biomarker activity and in vivo efficacy in a mouse xenograft model.
ComponentsHeat shock protein HSP 90-alphaHeat shock response
KeywordsCHAPERONE/CHAPERONE INHIBITOR / Chaperone / ATP binding domain / ATP-binding / Nucleotide-binding / Phosphoprotein / Stress response / 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 / chaperone-mediated autophagy / telomerase holoenzyme complex assembly / 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 / skeletal muscle contraction / regulation of protein ubiquitination / positive regulation of cell size / protein unfolding / HSF1-dependent transactivation / telomere maintenance via telomerase / response to unfolded protein / chaperone-mediated protein complex assembly / HSF1 activation / regulation of protein-containing complex assembly / Attenuation phase / RHOBTB2 GTPase cycle / positive regulation of lamellipodium assembly / eNOS activation / axonal growth cone / DNA polymerase binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / positive regulation of cardiac muscle contraction / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Signaling by ERBB2 / Recruitment of mitotic centrosome proteins and complexes / positive regulation of telomerase activity / response to salt stress / cardiac muscle cell apoptotic process / positive regulation of defense response to virus by host / endocytic vesicle lumen / Recruitment of NuMA to mitotic centrosomes / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / Anchoring of the basal body to the plasma membrane / protein tyrosine kinase binding / response to cold / activation of innate immune response / positive regulation of interferon-beta production / nitric-oxide synthase regulator activity / lysosomal lumen / Constitutive Signaling by Overexpressed ERBB2 / ESR-mediated signaling / AURKA Activation by TPX2 / VEGFR2 mediated vascular permeability / response to cocaine / brush border membrane / ATP-dependent protein folding chaperone / Signaling by ERBB2 TMD/JMD mutants / neuron migration / Constitutive Signaling by EGFRvIII / DDX58/IFIH1-mediated induction of interferon-alpha/beta / Signaling by ERBB2 ECD mutants / tau protein binding / Signaling by ERBB2 KD Mutants / Regulation of necroptotic cell death / Regulation of actin dynamics for phagocytic cup formation / cellular response to virus / Downregulation of ERBB2 signaling / 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 / regulation of protein localization / positive regulation of nitric oxide biosynthetic process / disordered domain specific binding / Regulation of PLK1 Activity at G2/M Transition / unfolded protein binding / melanosome
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-06J / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.5801 Å
AuthorsZapf, C.W. / Bloom, J.D. / McBean, J.L. / Dushin, R.G. / Golas, J.M. / Liu, H. / Lucas, J. / Boschelli, F. / Vogan, E.M. / Levin, J.I.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Discovery of a macrocyclic o-aminobenzamide Hsp90 inhibitor with heterocyclic tether that shows extended biomarker activity and in vivo efficacy in a mouse xenograft model.
Authors: Zapf, C.W. / Bloom, J.D. / McBean, J.L. / Dushin, R.G. / Golas, J.M. / Liu, H. / Lucas, J. / Boschelli, F. / Vogan, E. / Levin, J.I.
History
DepositionMar 24, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 8, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Apr 15, 2020Group: Data collection / Database references / Category: reflns / struct_ref_seq_dif
Item: _reflns.pdbx_Rmerge_I_obs / _struct_ref_seq_dif.details
Revision 1.3Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,8472
Polymers25,4131
Non-polymers4351
Water6,161342
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)67.350, 90.355, 98.594
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: 25412.568 Da / Num. of mol.: 1 / Fragment: N-terminal domain, UNP RESIDUES 10-236
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSP90A, HSP90AA1, HSPC1, HSPCA / Plasmid: pET28A / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P07900
#2: Chemical ChemComp-06J / (3aR)-13,13,16-trimethyl-15-oxo-1,2,3,3a,4,5,12,14,15,17,18,19-dodecahydro-13H-10,6-(metheno)pyrrolo[2',1':3,4][1,4,9]triazacyclotetradecino[9,8-a]indole-7-carboxamide


Mass: 434.574 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H34N4O2
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 342 / 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: 2.95 Å3/Da / Density % sol: 58.32 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 25% PEG3000, 0.1 M MES, pH 6.5, TEMPERATURE 277K; FROZEN BY 1-STEP TRANSFER TO 25% GLYCEROL, 19% PEG3000, 0.075M MES, VAPOR DIFFUSION, HANGING DROP

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU SATURN 92 / Detector: CCD / Date: May 30, 2008 / Details: mirros
RadiationMonochromator: Osmic mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.58→24.721 Å / Num. all: 41549 / Num. obs: 35263 / % possible obs: 84.87 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 6.6 % / Biso Wilson estimate: 17.638 Å2 / Rsym value: 0.045 / Net I/σ(I): 25.9
Reflection shellResolution: 1.58→1.62 Å / Redundancy: 1.3 % / Mean I/σ(I) obs: 1.12 / Num. unique all: 2676 / Rsym value: 0.501 / % possible all: 53.8

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Processing

Software
NameVersionClassification
StructureStudiodata collection
PHASERphasing
PHENIX(phenix.refine)refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.5801→24.721 Å / SU ML: 0.18 / σ(F): 0.01 / Phase error: 19.41 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1938 1805 5.12 %Random
Rwork0.1762 ---
obs0.1771 35263 84.87 %-
all-41549 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 51.737 Å2 / ksol: 0.369 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-0.7436 Å20 Å2-0 Å2
2--0.8489 Å2-0 Å2
3----1.7393 Å2
Refinement stepCycle: LAST / Resolution: 1.5801→24.721 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1635 0 32 342 2009
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0031721
X-RAY DIFFRACTIONf_angle_d0.7892332
X-RAY DIFFRACTIONf_dihedral_angle_d13.253638
X-RAY DIFFRACTIONf_chiral_restr0.057263
X-RAY DIFFRACTIONf_plane_restr0.002294
LS refinement shell

Refine-ID: X-RAY DIFFRACTION

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection obs% reflection obs (%)
1.5801-1.62280.3608920.28031247124742
1.6228-1.67050.2561970.25341754175459
1.6705-1.72440.25771240.2172246224675
1.7244-1.7860.20821230.21042483248382
1.786-1.85750.27771310.20492431243181
1.8575-1.9420.231400.1872522252284
1.942-2.04440.19711500.17382875287595
2.0444-2.17240.17041460.15992997299799
2.1724-2.340.19891850.17142929292997
2.34-2.57530.19551440.17412885288595
2.5753-2.94740.1881710.17232876287695
2.9474-3.71140.17591540.15963043304398
3.7114-24.72440.15331480.16283170317098

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