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- PDB-3qtf: Design and SAR of macrocyclic Hsp90 inhibitors with increased met... -

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Basic information

Entry
Database: PDB / ID: 3qtf
TitleDesign and SAR of macrocyclic Hsp90 inhibitors with increased metabolic stability and potent cell-proliferation activity
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 / regulation of protein ubiquitination / skeletal muscle contraction / positive regulation of cell size / HSF1-dependent transactivation / telomere maintenance via telomerase / response to unfolded protein / chaperone-mediated protein complex assembly / protein unfolding / 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 / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / positive regulation of cardiac muscle contraction / Recruitment of mitotic centrosome proteins and complexes / cardiac muscle cell apoptotic process / positive regulation of telomerase activity / Signaling by ERBB2 / positive regulation of defense response to virus by host / endocytic vesicle lumen / response to salt stress / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / activation of innate immune response / nitric-oxide synthase regulator activity / response to cold / positive regulation of interferon-beta production / lysosomal lumen / Constitutive Signaling by Overexpressed ERBB2 / AURKA Activation by TPX2 / ESR-mediated signaling / protein tyrosine kinase binding / 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 / histone deacetylase binding / Aggrephagy / Chaperone Mediated Autophagy / positive regulation of protein import into nucleus / response to estrogen / 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 / Regulation of PLK1 Activity at G2/M Transition / disordered domain specific binding / 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-05S / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.5703 Å
AuthorsZapf, C.W. / Bloom, J.D. / McBean, J.L. / Dushin, R.G. / Nittoli, T. / Ingalls, C. / Sutherland, A.G. / Sonye, J.P. / Eid, C.N. / Golas, J. ...Zapf, C.W. / Bloom, J.D. / McBean, J.L. / Dushin, R.G. / Nittoli, T. / Ingalls, C. / Sutherland, A.G. / Sonye, J.P. / Eid, C.N. / Golas, J. / Liu, H. / Boschelli, F. / Hu, Y. / Vogan, E.M. / Levin, J.I.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Design and SAR of macrocyclic Hsp90 inhibitors with increased metabolic stability and potent cell-proliferation activity.
Authors: Zapf, C.W. / Bloom, J.D. / McBean, J.L. / Dushin, R.G. / Nittoli, T. / Ingalls, C. / Sutherland, A.G. / Sonye, J.P. / Eid, C.N. / Golas, J. / Liu, H. / Boschelli, F. / Hu, Y. / Vogan, E. / Levin, J.I.
History
DepositionFeb 22, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 6, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Feb 21, 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)25,8993
Polymers25,4131
Non-polymers4872
Water5,603311
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)67.264, 90.718, 98.379
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-05S / (6S)-6,15,15,18-tetramethyl-17-oxo-2,3,4,5,6,7,14,15,16,17-decahydro-1H-8,12-(metheno)[1,4,9]triazacyclotetradecino[9,8-a]indole-9-carboxamide


Mass: 408.536 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H32N4O2
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 311 / 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: 58.34 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 18.4% PEG3350, 0.2M MAGNESIUM NITRATE, PROTEIN @ 13.5 MG/ML, TEMPERATURE 277K; FROZEN BY 1-STEP TRANSFER TO 25% GLYCEROL, 14% PEG3350, 0.15M MAGNESIUM NITRATE, pH 7.5, 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: Jun 27, 2008 / Details: mirrors
RadiationMonochromator: Osmic mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.57→22.7 Å / Num. all: 42430 / Num. obs: 32785 / % possible obs: 77.45 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 1

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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: 1.5703→22.68 Å / SU ML: 0.16 / Isotropic thermal model: isotropic / Cross valid method: THROUGHOUT / σ(F): 0 / Phase error: 21.99 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2042 1663 5.07 %Random
Rwork0.1873 ---
obs0.1882 32785 77.45 %-
all-42430 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 52.319 Å2 / ksol: 0.367 e/Å3
Displacement parametersBiso mean: 32.44 Å2
Baniso -1Baniso -2Baniso -3
1--5.4712 Å20 Å2-0 Å2
2--0.9318 Å2-0 Å2
3----4.7687 Å2
Refinement stepCycle: LAST / Resolution: 1.5703→22.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1626 0 34 311 1971
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0041705
X-RAY DIFFRACTIONf_angle_d0.8232306
X-RAY DIFFRACTIONf_dihedral_angle_d13.404629
X-RAY DIFFRACTIONf_chiral_restr0.06261
X-RAY DIFFRACTIONf_plane_restr0.003293
LS refinement shell

Refine-ID: X-RAY DIFFRACTION

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection obs% reflection obs (%)
1.5703-1.61650.3449520.29491149120134
1.6165-1.66870.27691050.25761714181952
1.6687-1.72830.24931140.23952229234367
1.7283-1.79750.2181280.23352226235468
1.7975-1.87920.28621000.2342033213361
1.8792-1.97830.24221700.20512948311889
1.9783-2.10210.19511560.19373090324693
2.1021-2.26430.21821740.18513147332194
2.2643-2.49190.2121710.19083079325092
2.4919-2.85190.2141810.18693149333095
2.8519-3.59080.16481670.17223327349497
3.5908-22.68190.17411450.15893031317686

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