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- PDB-5lo1: HSP90 WITH indazole derivative -

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Basic information

Entry
Database: PDB / ID: 5lo1
TitleHSP90 WITH indazole derivative
ComponentsHeat shock protein HSP 90-alpha
KeywordsCHAPERONE
Function / homology
Function and homology information


sperm plasma membrane / sperm mitochondrial sheath / sulfonylurea receptor binding / CTP binding / response to follicle-stimulating hormone / Scavenging by Class F Receptors / positive regulation of protein polymerization / vRNP Assembly / UTP binding / dATP binding ...sperm plasma membrane / sperm mitochondrial sheath / sulfonylurea receptor binding / CTP binding / response to follicle-stimulating hormone / Scavenging by Class F Receptors / positive regulation of protein polymerization / vRNP Assembly / UTP binding / dATP binding / mitochondrial transport / negative regulation of striated muscle cell apoptotic process / HSP90-CDC37 chaperone complex / AP-3 adaptor complex binding / telomerase holoenzyme complex assembly / chaperone-mediated autophagy / Respiratory syncytial virus genome replication / Rho GDP-dissociation inhibitor binding / 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 / Uptake and function of diphtheria toxin / positive regulation of cell size / dendritic growth cone / TPR domain binding / protein import into mitochondrial matrix / PIWI-interacting RNA (piRNA) biogenesis / response to dietary excess / response to caloric restriction / Assembly and release of respiratory syncytial virus (RSV) virions / non-chaperonin molecular chaperone ATPase / Sema3A PAK dependent Axon repulsion / response to salt stress / regulation of protein ubiquitination / response to unfolded protein / HSF1-dependent transactivation / cardiac muscle cell apoptotic process / regulation of protein-containing complex assembly / Attenuation phase / protein folding chaperone complex / HSF1 activation / enzyme-substrate adaptor activity / chaperone-mediated protein complex assembly / axonal growth cone / neurofibrillary tangle assembly / regulation of postsynaptic membrane neurotransmitter receptor levels / telomere maintenance via telomerase / positive regulation of lamellipodium assembly / RHOBTB2 GTPase cycle / Dengue virus activates/modulates innate and adaptive immune responses / nitric oxide metabolic process / response to isolation stress / protein unfolding / positive regulation of defense response to virus by host / Signaling by ERBB2 / skeletal muscle contraction / eNOS activation / positive regulation of telomere maintenance via telomerase / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / endocytic vesicle lumen / response to cold / DNA polymerase binding / 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 / cellular response to platelet-derived growth factor stimulus / lysosomal lumen / Recruitment of NuMA to mitotic centrosomes / ESR-mediated signaling / Anchoring of the basal body to the plasma membrane / activation of innate immune response / positive regulation of interferon-beta production / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / AURKA Activation by TPX2 / Constitutive Signaling by Overexpressed ERBB2 / protein tyrosine kinase binding / nitric-oxide synthase regulator activity / ATP-dependent protein folding chaperone / response to cocaine / VEGFR2 mediated vascular permeability / brush border membrane / cellular response to virus / positive regulation of protein import into nucleus / neuron migration / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / protein refolding / Regulation of actin dynamics for phagocytic cup formation / Signaling by ERBB2 KD Mutants / response to estrogen / VEGFA-VEGFR2 Pathway
Similarity search - Function
Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / Histidine kinase-like ATPase, C-terminal domain / Heat Shock Protein 90 / 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-, DNA gyrase B-, and HSP90-like ATPase ...Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / Histidine kinase-like ATPase, C-terminal domain / Heat Shock Protein 90 / 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-, 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-70L / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.7 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 1.3May 8, 2024Group: Advisory / Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_unobs_or_zero_occ_atoms
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)26,1292
Polymers25,7141
Non-polymers4151
Water30617
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area10150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.860, 92.360, 97.110
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-70L / 1-[2-Amino-4-(1,3-dihydro-isoindole-2-carbonyl)-quinazolin-6-yl]-cyclobutanecarboxylic acid ethylamide


Mass: 415.488 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H25N5O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 17 / 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: 2.87 Å3/Da / Density % sol: 57.17 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5 / Details: Bis-Tris Propan, pH 6.5 22% PEG 3350 0,2M NaF

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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: Dec 17, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.67→48.55 Å / Num. obs: 8553 / % possible obs: 97.6 % / Redundancy: 5.9 % / Biso Wilson estimate: 98.17 Å2 / Net I/σ(I): 17.2
Reflection shellResolution: 2.67→2.76 Å / Mean I/σ(I) obs: 2.9 / % possible all: 77.6

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
d*TREKdata reduction
d*TREKdata scaling
MOLREPphasing
RefinementResolution: 2.7→48.55 Å / Cor.coef. Fo:Fc: 0.93 / Cor.coef. Fo:Fc free: 0.938 / Rfactor Rfree error: 0.01 / SU R Cruickshank DPI: 0.541 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.547 / SU Rfree Blow DPI: 0.284 / SU Rfree Cruickshank DPI: 0.287
RfactorNum. reflection% reflectionSelection details
Rfree0.246 388 4.61 %RANDOM
Rwork0.233 ---
obs0.234 8411 99.5 %-
Displacement parametersBiso mean: 88.99 Å2
Baniso -1Baniso -2Baniso -3
1-8.0197 Å20 Å20 Å2
2---9.873 Å20 Å2
3---1.8533 Å2
Refine analyzeLuzzati coordinate error obs: 0.39 Å
Refinement stepCycle: 1 / Resolution: 2.7→48.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1465 0 31 17 1513
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.011582HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.192135HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d559SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes42HARMONIC2
X-RAY DIFFRACTIONt_gen_planes223HARMONIC5
X-RAY DIFFRACTIONt_it1582HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.94
X-RAY DIFFRACTIONt_other_torsion20.51
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion215SEMIHARMONIC5
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_contact1807SEMIHARMONIC4
LS refinement shellResolution: 2.7→3.02 Å / Rfactor Rfree error: 0 / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.304 110 4.73 %
Rwork0.264 2216 -
all0.266 2326 -
obs--98.94 %
Refinement TLS params.Method: refined / Origin x: -33.194 Å / Origin y: -15.5513 Å / Origin z: -20.107 Å
111213212223313233
T-0.2302 Å20.0202 Å2-0.044 Å2--0.1564 Å2-0.0318 Å2---0.2087 Å2
L6.6086 °2-0.9241 °2-0.9352 °2-3.0913 °21.6363 °2--4.6908 °2
S0.1078 Å °-0.0876 Å °0.2368 Å °-0.0806 Å °-0.0248 Å °-0.0804 Å °-0.2191 Å °-0.0031 Å °-0.083 Å °
Refinement TLS groupSelection details: { A|* }

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