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- PDB-5lnz: HSP90 WITH indazole derivative -

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Basic information

Entry
Database: PDB / ID: 5lnz
TitleHSP90 WITH indazole derivative
ComponentsHeat shock protein HSP 90-alpha
KeywordsCHAPERONE
Function / homology
Function and homology information


sulfonylurea receptor binding / sperm mitochondrial sheath / dATP binding / CTP binding / positive regulation of protein polymerization / vRNP Assembly / Scavenging by Class F Receptors / UTP binding / sperm plasma membrane / chaperone-mediated autophagy ...sulfonylurea receptor binding / sperm mitochondrial sheath / 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 / 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 / protein insertion into mitochondrial outer membrane / TPR domain binding / Assembly and release of respiratory syncytial virus (RSV) virions / non-chaperonin molecular chaperone ATPase / PIWI-interacting RNA (piRNA) biogenesis / dendritic growth cone / Sema3A PAK dependent Axon repulsion / protein unfolding / regulation of protein ubiquitination / HSF1-dependent transactivation / response to unfolded protein / positive regulation of cell size / enzyme-substrate adaptor activity / skeletal muscle contraction / HSF1 activation / regulation of protein-containing complex assembly / telomere maintenance via telomerase / regulation of postsynaptic membrane neurotransmitter receptor levels / 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 / Recruitment of mitotic centrosome proteins and complexes / nitric-oxide synthase regulator activity / activation of innate immune response / Recruitment of NuMA to mitotic centrosomes / lysosomal lumen / Anchoring of the basal body to the plasma membrane / positive regulation of interferon-beta production / response to cold / ESR-mediated signaling / Constitutive Signaling by Overexpressed ERBB2 / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / 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 / DDX58/IFIH1-mediated induction of interferon-alpha/beta / Signaling by ERBB2 KD Mutants / 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 / MHC class II protein complex binding / disordered domain specific 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/HSP90-like ATPase / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase superfamily / Ribosomal protein S5 domain 2-type fold / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-70Z / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.54 Å
AuthorsGraedler, U. / Amaral, M. / Schuetz, D.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Ligand Desolvation Steers On-Rate and Impacts Drug Residence Time of Heat Shock Protein 90 (Hsp90) Inhibitors.
Authors: Schuetz, D.A. / Richter, L. / Amaral, M. / Grandits, M. / Gradler, U. / Musil, D. / Buchstaller, H.P. / Eggenweiler, H.M. / Frech, M. / Ecker, G.F.
History
DepositionAug 8, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 29, 2017Provider: repository / Type: Initial release
Revision 1.1May 23, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jun 6, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)26,1792
Polymers25,7141
Non-polymers4661
Water6,738374
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area10330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)68.134, 91.107, 99.074
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: 25713.822 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSP90AA1, HSP90A, HSPC1, HSPCA / Production host: Escherichia coli (E. coli) / References: UniProt: P07900
#2: Chemical ChemComp-70Z / ~{N}3-butyl-~{N}3,~{N}5-dimethyl-~{N}5-(4-morpholin-4-ylphenyl)-6-oxidanyl-2~{H}-indazole-3,5-dicarboxamide


Mass: 465.545 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H31N5O4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 374 / 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: 2.99 Å3/Da / Density % sol: 58.86 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 28% PEG 400, 0.1 M Na Hepes pH 7.5, 0.2 M Calcium Chloride

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X1A / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Aug 20, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.54→70 Å / Num. obs: 45355 / % possible obs: 98.1 % / Redundancy: 5.56 % / Biso Wilson estimate: 25.22 Å2 / Rsym value: 0.07 / Net I/σ(I): 12.42
Reflection shellResolution: 1.54→1.63 Å / Mean I/σ(I) obs: 1.85 / % possible all: 89.1

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4EEH

4eeh


Resolution: 1.54→49.51 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.912 / Rfactor Rfree error: 0.01 / SU R Cruickshank DPI: 0.063 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.07 / SU Rfree Blow DPI: 0.071 / SU Rfree Cruickshank DPI: 0.065
RfactorNum. reflection% reflectionSelection details
Rfree0.198 2268 5 %RANDOM
Rwork0.172 ---
obs0.173 45348 98.8 %-
Displacement parametersBiso mean: 29.26 Å2
Baniso -1Baniso -2Baniso -3
1-0.2144 Å20 Å20 Å2
2---0.9963 Å20 Å2
3---0.7818 Å2
Refine analyzeLuzzati coordinate error obs: 0.18 Å
Refinement stepCycle: 1 / Resolution: 1.54→49.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1627 0 34 380 2041
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.011727HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.042334HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d607SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes46HARMONIC2
X-RAY DIFFRACTIONt_gen_planes245HARMONIC5
X-RAY DIFFRACTIONt_it1727HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.87
X-RAY DIFFRACTIONt_other_torsion13.75
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion229SEMIHARMONIC5
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_contact2326SEMIHARMONIC4
LS refinement shellResolution: 1.54→1.58 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.198 143 4.99 %
Rwork0.199 2721 -
all0.199 2864 -
obs--85.76 %
Refinement TLS params.Method: refined / Origin x: -0.5392 Å / Origin y: 14.6821 Å / Origin z: 29.0428 Å
111213212223313233
T-0.0233 Å20.0069 Å20.0169 Å2--0.0537 Å20.0157 Å2---0.0377 Å2
L0.9553 °2-0.2583 °20.0243 °2-0.6357 °2-0.1639 °2--0.9609 °2
S0.0105 Å °0.0544 Å °0.0582 Å °-0.0047 Å °-0.0136 Å °-0.0028 Å °-0.0588 Å °-0.0212 Å °0.0031 Å °
Refinement TLS groupSelection details: { A|* }

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