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- PDB-2yi7: Structural characterization of 5-Aryl-4-(5-substituted-2-4- dihyd... -

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Basic information

Entry
Database: PDB / ID: 2yi7
TitleStructural characterization of 5-Aryl-4-(5-substituted-2-4- dihydroxyphenyl)-1,2,3-thiadiazole Hsp90 inhibitors.
ComponentsHEAT SHOCK PROTEIN HSP 90-ALPHA
KeywordsCHAPERONE / ATPASE
Function / homology
Function and homology information


sperm mitochondrial sheath / sulfonylurea receptor binding / dATP binding / CTP binding / positive regulation of protein polymerization / Scavenging by Class F Receptors / vRNP Assembly / UTP binding / chaperone-mediated autophagy / sperm plasma membrane ...sperm mitochondrial sheath / sulfonylurea receptor binding / dATP binding / CTP binding / positive regulation of protein polymerization / Scavenging by Class F Receptors / vRNP Assembly / UTP binding / chaperone-mediated autophagy / sperm plasma membrane / Respiratory syncytial virus genome replication / Rho GDP-dissociation inhibitor binding / telomerase holoenzyme complex assembly / 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 / Uptake and function of diphtheria toxin / protein import into mitochondrial matrix / TPR domain binding / dendritic growth cone / PIWI-interacting RNA (piRNA) biogenesis / Assembly and release of respiratory syncytial virus (RSV) virions / non-chaperonin molecular chaperone ATPase / protein unfolding / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / positive regulation of cell size / HSF1-dependent transactivation / protein folding chaperone complex / enzyme-substrate adaptor activity / response to unfolded protein / regulation of protein-containing complex assembly / HSF1 activation / Attenuation phase / chaperone-mediated protein complex assembly / neurofibrillary tangle assembly / RHOBTB2 GTPase cycle / regulation of postsynaptic membrane neurotransmitter receptor levels / axonal growth cone / telomere maintenance via telomerase / skeletal muscle contraction / positive regulation of lamellipodium assembly / nitric oxide metabolic process / response to salt stress / positive regulation of defense response to virus by host / DNA polymerase binding / eNOS activation / positive regulation of telomere maintenance via telomerase / Signaling by ERBB2 / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / cardiac muscle cell apoptotic process / 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 / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / activation of innate immune response / lysosomal lumen / ESR-mediated signaling / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / positive regulation of interferon-beta production / protein tyrosine kinase binding / Constitutive Signaling by Overexpressed ERBB2 / response to cold / AURKA Activation by TPX2 / nitric-oxide synthase regulator activity / VEGFR2 mediated vascular permeability / response to cocaine / ATP-dependent protein folding chaperone / brush border membrane / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / DDX58/IFIH1-mediated induction of interferon-alpha/beta / positive regulation of protein import into nucleus / cellular response to virus / Regulation of actin dynamics for phagocytic cup formation / Regulation of necroptotic cell death / response to estrogen / VEGFA-VEGFR2 Pathway / extracellular matrix / tau protein binding / Downregulation of ERBB2 signaling / neuron migration / histone deacetylase binding / Chaperone Mediated Autophagy / disordered domain specific binding / positive regulation of nitric oxide biosynthetic process / Aggrephagy
Similarity search - Function
Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / Histidine kinase-like ATPase, C-terminal domain / HSP90, C-terminal domain / Heat shock protein Hsp90, N-terminal / Heat Shock Protein 90 / Heat shock protein Hsp90 family / Hsp90 protein / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase/HSP90-like ATPase ...Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / Histidine kinase-like ATPase, C-terminal domain / HSP90, C-terminal domain / Heat shock protein Hsp90, N-terminal / Heat Shock Protein 90 / Heat shock protein Hsp90 family / Hsp90 protein / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase/HSP90-like ATPase / Histidine kinase-, DNA gyrase B-, and 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-BZ8 / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 Å
AuthorsRoe, S.M. / Prodromou, C. / Pearl, L.H.
CitationJournal: Plos One / Year: 2012
Title: Co-Crystalization and in Vitro Biological Characterization of 5-Aryl-4-(5-Substituted-2-4-Dihydroxyphenyl)-1,2,3-Thiadiazole Hsp90 Inhibitors.
Authors: Sharp, S.Y. / Roe, S.M. / Kazlauskas, E. / Cikotiene, I. / Workman, P. / Matulis, D. / Prodromou, C.
History
DepositionMay 10, 2011Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 16, 2012Provider: repository / Type: Initial release
Revision 1.1Sep 26, 2012Group: Database references
Revision 1.2May 1, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_symmetry / _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)26,2293
Polymers25,8561
Non-polymers3732
Water6,593366
1
A: HEAT SHOCK PROTEIN HSP 90-ALPHA
hetero molecules

A: HEAT SHOCK PROTEIN HSP 90-ALPHA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,4586
Polymers51,7122
Non-polymers7464
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_655-x+1,-y,z1
Buried area1820 Å2
ΔGint-26.5 kcal/mol
Surface area18970 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.230, 88.705, 99.625
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 / HSP90 / HEAT SHOCK 86 KDA / HSP 86 / HSP86 / RENAL CARCINOMA ANTIGEN NY-REN-38


Mass: 25856.082 Da / Num. of mol.: 1 / Fragment: N-TERMINAL DOMAIN, RESIDUES 1-229
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P07900
#2: Chemical ChemComp-BZ8 / 4-CHLORO-6-[5-(4-ETHOXYPHENYL)-1,2,3-THIADIAZOL-4-YL BENZENE-1,3-DIOL


Mass: 348.804 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H13ClN2O3S
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 366 / 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: 2.9 Å3/Da / Density % sol: 58 % / Description: NONE
Crystal growpH: 7 / Details: pH 7

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.9796
DetectorType: ADSC CCD / Detector: CCD / Date: May 27, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9796 Å / Relative weight: 1
ReflectionResolution: 1.4→45 Å / Num. obs: 57073 / % possible obs: 99.8 % / Observed criterion σ(I): 0 / Redundancy: 4.2 % / Biso Wilson estimate: 19.5 Å2 / Rmerge(I) obs: 0.05 / Net I/σ(I): 18.3
Reflection shellResolution: 1.4→1.48 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.39 / Mean I/σ(I) obs: 3.3 / % possible all: 99.8

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Processing

Software
NameVersionClassification
REFMAC5.5.0109refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: INTERNAL STRUCTURE

Resolution: 1.4→44.35 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.965 / SU B: 1.745 / SU ML: 0.034 / Cross valid method: THROUGHOUT / ESU R: 0.053 / ESU R Free: 0.054 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.19635 2895 5.1 %RANDOM
Rwork0.17478 ---
obs0.1759 54114 99.79 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 24.377 Å2
Baniso -1Baniso -2Baniso -3
1--0.02 Å20 Å20 Å2
2---0.08 Å20 Å2
3---0.1 Å2
Refinement stepCycle: LAST / Resolution: 1.4→44.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1632 0 24 366 2022
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0320.0221715
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg2.6831.9832325
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.2255220
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.84225.06873
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.15615315
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.779157
X-RAY DIFFRACTIONr_chiral_restr0.1790.2268
X-RAY DIFFRACTIONr_gen_planes_refined0.0170.021268
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.4911.51051
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.39121704
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.7253664
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it5.5194.5615
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.4→1.436 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.394 228 -
Rwork0.386 3927 -
obs--99.93 %
Refinement TLS params.Method: refined / Origin x: 31.714 Å / Origin y: 14.472 Å / Origin z: 20.262 Å
111213212223313233
T0.0341 Å2-0.0019 Å20.005 Å2-0.0174 Å2-0.0147 Å2--0.014 Å2
L2.3532 °20.4124 °20.1671 °2-1.3054 °2-0.1098 °2--1.6884 °2
S0.0397 Å °0.0348 Å °-0.004 Å °0.0198 Å °-0.0185 Å °0.0234 Å °-0.0115 Å °0.0149 Å °-0.0212 Å °

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