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Basic information

Entry
Database: PDB / ID: 6tn5
TitleRapid optimisation of fragments and hits to lead compounds from screening of crude reaction mixtures
ComponentsHeat shock protein HSP 90-alpha
KeywordsCHAPERONE / OFF-RATE SCREENING / PDHK / HSP90 / SPR / KINASE INHIBITORS / FRAGMENT SCREENING / CANCER / PDK2 / TRANSFERASE
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 / chaperone-mediated autophagy / telomerase holoenzyme complex assembly / protein insertion into mitochondrial outer membrane / Respiratory syncytial virus genome replication / Uptake and function of diphtheria toxin / Rho GDP-dissociation inhibitor binding / 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 / Assembly and release of respiratory syncytial virus (RSV) virions / regulation of postsynaptic membrane neurotransmitter receptor levels / dendritic growth cone / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / skeletal muscle contraction / HSF1-dependent transactivation / positive regulation of cell size / response to unfolded protein / telomere maintenance via telomerase / chaperone-mediated protein complex assembly / protein unfolding / HSF1 activation / regulation of protein-containing complex assembly / Attenuation phase / RHOBTB2 GTPase cycle / eNOS activation / axonal growth cone / positive regulation of lamellipodium assembly / 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 / Recruitment of mitotic centrosome proteins and complexes / positive regulation of telomerase activity / Signaling by ERBB2 / cardiac muscle cell apoptotic process / positive regulation of defense response to virus by host / positive regulation of cardiac muscle contraction / endocytic vesicle lumen / Recruitment of NuMA to mitotic centrosomes / response to salt stress / 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 / positive regulation of interferon-beta production / response to cold / Constitutive Signaling by Overexpressed ERBB2 / AURKA Activation by TPX2 / lysosomal lumen / 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 / DDX58/IFIH1-mediated induction of interferon-alpha/beta / Constitutive Signaling by EGFRvIII / 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 / Regulation of PLK1 Activity at G2/M Transition / positive regulation of nitric oxide biosynthetic process / disordered domain specific binding
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-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-like ATPases / Histidine kinase/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-, 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
Similarity search - Domain/homology
Chem-NL8 / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MIR / Resolution: 1.165 Å
AuthorsBaker, L.M. / Aimon, A. / Murray, J.B. / Surgenor, A.E. / Matassova, N. / Roughley, S.D. / von Delft, F. / Hubbard, R.E.
CitationJournal: Commun Chem / Year: 2020
Title: Rapid optimisation of fragments and hits to lead compounds from screening of crude reaction mixtures
Authors: Baker, L.M. / Aimon, A. / Murray, J.B. / Surgenor, A.E. / Matassova, N. / Roughley, S.D. / Collins, P.M. / Krojer, T. / von Delft, F. / Hubbard, R.E.
History
DepositionDec 5, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 14, 2020Provider: repository / Type: Initial release
Revision 1.1May 15, 2024Group: Data collection / Database references / Derived calculations
Category: atom_type / chem_comp_atom ...atom_type / chem_comp_atom / chem_comp_bond / database_2
Item: _atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z ..._atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)26,2483
Polymers25,9261
Non-polymers3222
Water7,116395
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area110 Å2
ΔGint-8 kcal/mol
Surface area10180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.720, 89.530, 100.025
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11AAA-667-

HOH

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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: 25926.111 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSP90AA1, HSP90A, HSPC1, HSPCA / Plasmid: PET19 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): pLysS / References: UniProt: P07900
#2: Chemical ChemComp-NL8 / ~{N}-(4-aminocarbonylphenyl)-~{N}-methyl-2,4-bis(oxidanyl)benzamide


Mass: 286.283 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H14N2O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 395 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.84 Å3/Da / Density % sol: 56.65 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 10% PEG3350, 0.1 M sodium cacodylate pH 6.5, 0.2 M MgCl2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.91587 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Oct 10, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91587 Å / Relative weight: 1
ReflectionResolution: 1.165→54.925 Å / Num. obs: 78794 / % possible obs: 91.1 % / Redundancy: 6.1 % / CC1/2: 0.999 / Rmerge(I) obs: 0.057 / Net I/σ(I): 14
Reflection shellResolution: 1.165→1.247 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.654 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 3941 / CC1/2: 0.686 / % possible all: 60.9

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
xia2data reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: MIR / Resolution: 1.165→54.925 Å / Cor.coef. Fo:Fc: 0.975 / Cor.coef. Fo:Fc free: 0.967 / Cross valid method: FREE R-VALUE / ESU R: 0.039 / ESU R Free: 0.04
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.1836 3900 4.948 %
Rwork0.1687 --
all0.169 --
obs-74921 77.335 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 16.209 Å2
Baniso -1Baniso -2Baniso -3
1--0.002 Å2-0 Å2-0 Å2
2--0.012 Å20 Å2
3----0.009 Å2
Refinement stepCycle: LAST / Resolution: 1.165→54.925 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1633 0 22 395 2050
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0131767
X-RAY DIFFRACTIONr_bond_other_d0.0350.0171640
X-RAY DIFFRACTIONr_angle_refined_deg2.1591.6572408
X-RAY DIFFRACTIONr_angle_other_deg2.3871.5843828
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1825233
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.90524.09188
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.4415324
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.293157
X-RAY DIFFRACTIONr_chiral_restr0.1110.2245
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.021995
X-RAY DIFFRACTIONr_gen_planes_other0.0160.02358
X-RAY DIFFRACTIONr_nbd_refined0.2480.2400
X-RAY DIFFRACTIONr_symmetry_nbd_other0.2160.21595
X-RAY DIFFRACTIONr_nbtor_refined0.1780.2890
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0780.2790
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2510.2277
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.4640.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.070.211
X-RAY DIFFRACTIONr_nbd_other0.2040.226
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2940.230
X-RAY DIFFRACTIONr_mcbond_it1.7021.404861
X-RAY DIFFRACTIONr_mcbond_other1.6881.401860
X-RAY DIFFRACTIONr_mcangle_it2.5932.1081081
X-RAY DIFFRACTIONr_mcangle_other2.5992.1111082
X-RAY DIFFRACTIONr_scbond_it2.7731.657906
X-RAY DIFFRACTIONr_scbond_other2.7741.657905
X-RAY DIFFRACTIONr_scangle_it3.942.3861314
X-RAY DIFFRACTIONr_scangle_other3.9382.3861315
X-RAY DIFFRACTIONr_lrange_it6.06919.8042266
X-RAY DIFFRACTIONr_lrange_other5.6917.9992124
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.165-1.190.474270.349474X-RAY DIFFRACTION6.714
1.19-1.2220.278570.3211476X-RAY DIFFRACTION21.0375
1.222-1.2580.2891220.2732484X-RAY DIFFRACTION36.9017
1.258-1.2970.2521980.2763752X-RAY DIFFRACTION57.3128
1.297-1.3390.2863250.2745726X-RAY DIFFRACTION90.611
1.339-1.3860.263010.2486103X-RAY DIFFRACTION98.9799
1.386-1.4380.2542840.225939X-RAY DIFFRACTION99.6637
1.438-1.4970.2113200.1945689X-RAY DIFFRACTION99.7676
1.497-1.5640.1872780.1735476X-RAY DIFFRACTION99.9132
1.564-1.640.1812830.1675236X-RAY DIFFRACTION99.9457
1.64-1.7290.1962520.1675033X-RAY DIFFRACTION99.9811
1.729-1.8330.1642480.1634714X-RAY DIFFRACTION99.9396
1.833-1.960.1672110.1544014X-RAY DIFFRACTION89.9319
1.96-2.1170.1711560.1663219X-RAY DIFFRACTION77.2488
2.117-2.3180.1551850.1443568X-RAY DIFFRACTION92.5524
2.318-2.5920.1692010.1433456X-RAY DIFFRACTION99.918
2.592-2.9920.151440.1552864X-RAY DIFFRACTION91.9596
2.992-3.6620.1961510.1482501X-RAY DIFFRACTION96.2264
3.662-5.1720.1521000.1421991X-RAY DIFFRACTION95.6979
5.172-54.9250.214570.2081206X-RAY DIFFRACTION98.8263

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