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- PDB-3r91: Macrocyclic lactams as potent Hsp90 inhibitors with excellent tum... -

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Basic information

Entry
Database: PDB / ID: 3r91
TitleMacrocyclic lactams as potent Hsp90 inhibitors with excellent tumor exposure and extended biomarker activity.
ComponentsHeat shock protein HSP 90-alpha
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 / 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 / Recruitment of NuMA to mitotic centrosomes / activation of innate immune response / Anchoring of the basal body to the plasma membrane / lysosomal lumen / positive regulation of interferon-beta production / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / response to cold / 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-06H / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.579 Å
AuthorsZapf, C.W. / Bloom, J.D. / McBean, J.L. / Dushin, R.G. / Nittoli, T. / Otteng, M. / Ingalls, C. / Golas, J.M. / Liu, H. / Lucas, J. ...Zapf, C.W. / Bloom, J.D. / McBean, J.L. / Dushin, R.G. / Nittoli, T. / Otteng, M. / Ingalls, C. / Golas, J.M. / Liu, H. / Lucas, J. / Boschelli, F. / Vogan, E. / Hu, Y. / Levin, J.I.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Macrocyclic lactams as potent Hsp90 inhibitors with excellent tumor exposure and extended biomarker activity.
Authors: Zapf, C.W. / Bloom, J.D. / McBean, J.L. / Dushin, R.G. / Nittoli, T. / Otteng, M. / Ingalls, C. / Golas, J.M. / Liu, H. / Lucas, J. / Boschelli, F. / Hu, Y. / Vogan, E. / Levin, J.I.
History
DepositionMar 24, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 11, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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)25,8492
Polymers25,4131
Non-polymers4371
Water5,585310
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)67.042, 90.250, 97.797
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11A-472-

HOH

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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: 25412.568 Da / Num. of mol.: 1 / Fragment: N-terminal domain, UNP RESIDUES 10-236 / Mutation: Delta 16
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-06H / (6S)-4,6,15,15,18-pentamethyl-5,17-dioxo-2,3,4,5,6,7,14,15,16,17-decahydro-1H-12,8-(metheno)[1,4,9]triazacyclotetradecino[9,8-a]indole-9-carboxamide


Mass: 436.547 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H32N4O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 310 / 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: 2.91 Å3/Da / Density % sol: 57.74 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 22% PEG3350, 0.175 M MAGNESIUM NITRATE, pH 7.5, TEMPERATURE 277K; FROZEN BY 1-STEP TRANSFER TO 25% GLYCEROL, 17% PEG3350, 0.13M MAGNESIUM NITRATE, 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 29, 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: 1.579→27.65 Å / Num. all: 41054 / Num. obs: 30881 / % possible obs: 75.22 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 7.5 % / Biso Wilson estimate: 19.38 Å2 / Rsym value: 0.052 / Net I/σ(I): 27.4
Reflection shellResolution: 1.579→1.62 Å / Redundancy: 1.3 % / Mean I/σ(I) obs: 1.35 / Num. unique all: 2677 / Rsym value: 0.389 / % possible all: 44

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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
Starting model: PDB ENTRY 3BM9

3bm9


Resolution: 1.579→27.648 Å / SU ML: 0.18 / σ(F): 0.01 / σ(I): 0 / Phase error: 21.14 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1988 1589 5.15 %Random
Rwork0.1863 ---
obs0.1869 30881 75.22 %-
all-41054 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 39.767 Å2 / ksol: 0.365 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--4.4254 Å20 Å2-0 Å2
2--1.1597 Å2-0 Å2
3----1.2267 Å2
Refinement stepCycle: LAST / Resolution: 1.579→27.648 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1626 0 32 310 1968
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0061688
X-RAY DIFFRACTIONf_angle_d1.0092284
X-RAY DIFFRACTIONf_dihedral_angle_d14.412615
X-RAY DIFFRACTIONf_chiral_restr0.07258
X-RAY DIFFRACTIONf_plane_restr0.004290
LS refinement shell

Refine-ID: X-RAY DIFFRACTION

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection obs% reflection obs (%)
1.579-1.630.2985600.25821145114533
1.63-1.68820.2342990.23821690169049
1.6882-1.75580.2581220.22912155215562
1.7558-1.83570.26131260.21852254225465
1.8357-1.93250.25151280.2092384238468
1.9325-2.05350.19061640.18642971297184
2.0535-2.2120.18411680.17693268326892
2.212-2.43450.20811810.19193149314990
2.4345-2.78650.21431790.20183230323091
2.7865-3.50950.20931800.18183434343495
3.5095-27.65240.15641820.16323612361297

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