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- PDB-4fcp: Targetting conserved water molecules: Design of 4-aryl-5-cyanopyr... -

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Basic information

Entry
Database: PDB / ID: 4fcp
TitleTargetting conserved water molecules: Design of 4-aryl-5-cyanopyrrolo [2,3-d] pyrimidine Hsp90 inhibitors using fragment-based screening and structure-based optimization
ComponentsHeat shock protein HSP 90-alpha
KeywordsCHAPERONE / Hsp90 / Heat Shock Protein / ATPase / Structure-based ligand design / fragment structural studies
Function / homology
Function and homology information


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 / 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 / protein insertion into mitochondrial outer membrane / chaperone-mediated autophagy / telomerase holoenzyme complex assembly / Respiratory syncytial virus genome replication / Rho GDP-dissociation inhibitor binding / Uptake and function of diphtheria toxin / 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 / dendritic growth cone / regulation of postsynaptic membrane neurotransmitter receptor levels / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / skeletal muscle contraction / telomere maintenance via telomerase / protein unfolding / HSF1-dependent transactivation / response to unfolded protein / positive regulation of cell size / chaperone-mediated protein complex assembly / regulation of protein-containing complex assembly / HSF1 activation / Attenuation phase / RHOBTB2 GTPase cycle / positive regulation of lamellipodium assembly / axonal growth cone / eNOS activation / DNA polymerase binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / positive regulation of defense response to virus by host / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / Signaling by ERBB2 / response to salt stress / cardiac muscle cell apoptotic process / endocytic vesicle lumen / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / positive regulation of cardiac muscle contraction / activation of innate immune response / nitric-oxide synthase regulator activity / positive regulation of interferon-beta production / response to cold / AURKA Activation by TPX2 / lysosomal lumen / Constitutive Signaling by Overexpressed ERBB2 / ESR-mediated signaling / protein tyrosine kinase binding / VEGFR2 mediated vascular permeability / response to cocaine / ATP-dependent protein folding chaperone / Signaling by ERBB2 TMD/JMD mutants / brush border membrane / neuron migration / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / DDX58/IFIH1-mediated induction of interferon-alpha/beta / Signaling by ERBB2 KD Mutants / tau protein binding / Regulation of necroptotic cell death / cellular response to virus / Regulation of actin dynamics for phagocytic cup formation / Downregulation of ERBB2 signaling / VEGFA-VEGFR2 Pathway / histone deacetylase binding / positive regulation of protein import into nucleus / Aggrephagy / Chaperone Mediated Autophagy / response to estrogen / positive regulation of protein catabolic process / The role of GTSE1 in G2/M progression after G2 checkpoint / disordered domain specific binding / positive regulation of nitric oxide biosynthetic process / Regulation of PLK1 Activity at G2/M Transition / unfolded protein binding / melanosome
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-like ATPase, C-terminal domain / Heat Shock Protein 90 / 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-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-like ATPase, C-terminal domain / Heat Shock Protein 90 / 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
N,N-dimethyl-7H-purin-6-amine / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsDavies, N.G.M. / Browne, H. / Davies, B. / Foloppe, N. / Geoffrey, S. / Gibbons, B. / Hart, T. / Drysdale, M. / Mansell, H. / Massey, A. ...Davies, N.G.M. / Browne, H. / Davies, B. / Foloppe, N. / Geoffrey, S. / Gibbons, B. / Hart, T. / Drysdale, M. / Mansell, H. / Massey, A. / Matassova, N. / Moore, J.D. / Murray, J. / Pratt, R. / Ray, S. / Roughley, S.D. / Jensen, M.R. / Schoepfer, J. / Scriven, K. / Simmonite, H. / Stokes, S. / Surgenor, A. / Webb, P. / Wright, L. / Brough, P.
CitationJournal: Bioorg.Med.Chem. / Year: 2012
Title: Targeting conserved water molecules: Design of 4-aryl-5-cyanopyrrolo[2,3-d]pyrimidine Hsp90 inhibitors using fragment-based screening and structure-based optimization.
Authors: Davies, N.G. / Browne, H. / Davis, B. / Drysdale, M.J. / Foloppe, N. / Geoffrey, S. / Gibbons, B. / Hart, T. / Hubbard, R. / Jensen, M.R. / Mansell, H. / Massey, A. / Matassova, N. / Moore, ...Authors: Davies, N.G. / Browne, H. / Davis, B. / Drysdale, M.J. / Foloppe, N. / Geoffrey, S. / Gibbons, B. / Hart, T. / Hubbard, R. / Jensen, M.R. / Mansell, H. / Massey, A. / Matassova, N. / Moore, J.D. / Murray, J. / Pratt, R. / Ray, S. / Robertson, A. / Roughley, S.D. / Schoepfer, J. / Scriven, K. / Simmonite, H. / Stokes, S. / Surgenor, A. / Webb, P. / Wood, M. / Wright, L. / Brough, P.
History
DepositionMay 25, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 24, 2012Provider: repository / Type: Initial release
Revision 1.1Nov 7, 2012Group: Database references
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_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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
B: Heat shock protein HSP 90-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,5304
Polymers53,2042
Non-polymers3262
Water6,774376
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
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)53,5304
Polymers53,2042
Non-polymers3262
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,-y,z1
Buried area1900 Å2
ΔGint-15 kcal/mol
Surface area18490 Å2
MethodPISA
3
B: Heat shock protein HSP 90-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,7652
Polymers26,6021
Non-polymers1631
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)64.170, 88.686, 98.629
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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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: 26601.773 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Cloned From Image:4026275 / Source: (gene. exp.) Homo sapiens (human) / Gene: HSP90AA1, HSP90A, HSPC1, HSPCA / Plasmid: PET19 / Production host: Escherichia coli (E. coli) / Strain (production host): Bl21(DE3) / References: UniProt: P07900
#2: Chemical ChemComp-42C / N,N-dimethyl-7H-purin-6-amine


Mass: 163.180 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C7H9N5
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 376 / 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: 2.64 Å3/Da / Density % sol: 53.36 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 25% PEG MME 2000, 0.1M NA CACODYLATE 6.5, 0.2M MGCL2, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5412 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Apr 1, 2005 / Details: Osmic blue mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5412 Å / Relative weight: 1
ReflectionResolution: 2→30 Å / Num. all: 93523 / Num. obs: 35244 / % possible obs: 90.9 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Rmerge(I) obs: 0.116 / Net I/σ(I): 6.1
Reflection shellResolution: 2→2.06 Å / Rmerge(I) obs: 0.32 / Mean I/σ(I) obs: 2.8 / % possible all: 70

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Processing

Software
NameVersionClassification
CrystalCleardata collection
AMoREphasing
REFMAC5.1.24refinement
d*TREKdata reduction
d*TREKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1UYM

1uym


Resolution: 2→20 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.902 / SU B: 5.757 / SU ML: 0.143 / Cross valid method: THROUGHOUT / σ(F): 2 / σ(I): 2 / ESU R: 0.222 / ESU R Free: 0.203 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.29153 1754 5 %RANDOM
Rwork0.23938 ---
all0.247 93523 --
obs0.24191 33476 90.87 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 28.516 Å2
Baniso -1Baniso -2Baniso -3
1-0.05 Å20 Å20 Å2
2--0.07 Å20 Å2
3----0.13 Å2
Refinement stepCycle: LAST / Resolution: 2→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3262 0 24 376 3662
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.023342
X-RAY DIFFRACTIONr_angle_refined_deg2.1161.9724510
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.0445414
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.75625.135148
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.25115612
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.6171514
X-RAY DIFFRACTIONr_chiral_restr0.1360.2516
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.022474
LS refinement shellResolution: 2→2.051 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.426 85 -
Rwork0.431 1767 -
obs--66.84 %

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