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- PDB-5zr3: Crystal structure of Hsp90-alpha N-terminal domain in complex wit... -

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Basic information

Entry
Database: PDB / ID: 5zr3
TitleCrystal structure of Hsp90-alpha N-terminal domain in complex with 4-(3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)-3-methylbenzamide
ComponentsHeat shock protein HSP 90-alphaHeat shock response
KeywordsCHAPERONE / Inhibitor / Complex
Function / homology
Function and homology information


Scavenging by Class F Receptors / positive regulation of protein polymerization / vRNP Assembly / telomerase holoenzyme complex assembly / protein insertion into mitochondrial outer membrane / Uptake and function of diphtheria toxin / chaperone-mediated autophagy / central nervous system neuron axonogenesis / mitochondrial transport / Resistance of ERBB2 KD mutants to neratinib ...Scavenging by Class F Receptors / positive regulation of protein polymerization / vRNP Assembly / telomerase holoenzyme complex assembly / protein insertion into mitochondrial outer membrane / Uptake and function of diphtheria toxin / chaperone-mediated autophagy / central nervous system neuron axonogenesis / mitochondrial transport / Resistance of ERBB2 KD mutants to neratinib / Drug-mediated inhibition of ERBB2 signaling / Resistance of ERBB2 KD mutants to sapitinib / Resistance of ERBB2 KD mutants to tesevatinib / Resistance of ERBB2 KD mutants to trastuzumab / 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 / Resistance of ERBB2 KD mutants to osimertinib / positive regulation of protein catabolic process => GO:0045732 / TPR domain binding / PIWI-interacting RNA (piRNA) biogenesis / non-chaperonin molecular chaperone ATPase / dendritic growth cone / regulation of protein ubiquitination / protein unfolding / chaperone-mediated protein complex assembly / axon extension / Sema3A PAK dependent Axon repulsion / telomere maintenance via telomerase / positive regulation of tau-protein kinase activity / RHOBTB2 GTPase cycle / HSF1-dependent transactivation / response to unfolded protein / HSF1 activation / DNA polymerase binding / regulation of protein-containing complex assembly / Attenuation phase / axonal growth cone / eNOS activation / establishment of cell polarity / positive regulation of defense response to virus by host / Loss of proteins required for interphase microtubule organization from the centrosome / Loss of Nlp from mitotic centrosomes / Recruitment of mitotic centrosome proteins and complexes / protein tyrosine kinase binding / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / response to cold / Recruitment of NuMA to mitotic centrosomes / Signaling by ERBB2 / Anchoring of the basal body to the plasma membrane / activation of innate immune response / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / protein folding chaperone / endocytic vesicle lumen / positive regulation of telomerase activity / positive regulation of interferon-beta production / lysosomal lumen / AURKA Activation by TPX2 / nitric-oxide synthase regulator activity / Constitutive Signaling by Overexpressed ERBB2 / ESR-mediated signaling / VEGFR2 mediated vascular permeability / Signaling by ERBB2 TMD/JMD mutants / tau protein binding / GTPase binding / DDX58/IFIH1-mediated induction of interferon-alpha/beta / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Regulation of necroptotic cell death / Signaling by ERBB2 KD Mutants / Downregulation of ERBB2 signaling / Aggrephagy / cellular response to virus / VEGFA-VEGFR2 Pathway / Regulation of actin dynamics for phagocytic cup formation / Chaperone Mediated Autophagy / histone deacetylase binding / melanosome / regulation of protein localization / The role of GTSE1 in G2/M progression after G2 checkpoint / Regulation of PLK1 Activity at G2/M Transition / unfolded protein binding / protein folding / positive regulation of nitric oxide biosynthetic process / Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants / cellular response to heat / disordered domain specific binding / scaffold protein binding / myelin sheath / MHC class II protein complex binding / Potential therapeutics for SARS / Extra-nuclear estrogen signaling / protein refolding / positive regulation of peptidyl-serine phosphorylation / response to heat / secretory granule lumen / Estrogen-dependent gene expression / Interleukin-4 and Interleukin-13 signaling / protein stabilization
Similarity search - Function
Heat shock hsp90 proteins family signature. / Heat shock protein Hsp90, conserved site / Heat shock protein Hsp90, N-terminal / Heat shock protein Hsp90 family / HSP90, C-terminal domain / Hsp90 protein / Histidine kinase-like ATPase, C-terminal domain / Heat Shock Protein 90 / Histidine kinase-like ATPases / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase ...Heat shock hsp90 proteins family signature. / Heat shock protein Hsp90, conserved site / Heat shock protein Hsp90, N-terminal / Heat shock protein Hsp90 family / HSP90, C-terminal domain / Hsp90 protein / Histidine kinase-like ATPase, C-terminal domain / Heat Shock Protein 90 / Histidine kinase-like ATPases / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / 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-9J0 / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.5 Å
AuthorsUno, T. / Chong, K.T. / Suzuki, T.
CitationJournal: J. Med. Chem. / Year: 2019
Title: Discovery of 3-Ethyl-4-(3-isopropyl-4-(4-(1-methyl-1 H-pyrazol-4-yl)-1 H-imidazol-1-yl)-1 H-pyrazolo[3,4- b]pyridin-1-yl)benzamide (TAS-116) as a Potent, Selective, and Orally Available HSP90 Inhibitor.
Authors: Uno, T. / Kawai, Y. / Yamashita, S. / Oshiumi, H. / Yoshimura, C. / Mizutani, T. / Suzuki, T. / Chong, K.T. / Shigeno, K. / Ohkubo, M. / Kodama, Y. / Muraoka, H. / Funabashi, K. / Takahashi, ...Authors: Uno, T. / Kawai, Y. / Yamashita, S. / Oshiumi, H. / Yoshimura, C. / Mizutani, T. / Suzuki, T. / Chong, K.T. / Shigeno, K. / Ohkubo, M. / Kodama, Y. / Muraoka, H. / Funabashi, K. / Takahashi, K. / Ohkubo, S. / Kitade, M.
History
DepositionApr 23, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 2, 2019Provider: repository / Type: Initial release
Revision 1.1May 1, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year

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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
C: Heat shock protein HSP 90-alpha
E: Heat shock protein HSP 90-alpha
G: Heat shock protein HSP 90-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)108,7228
Polymers106,9604
Non-polymers1,7624
Water1,838102
1
A: Heat shock protein HSP 90-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,1802
Polymers26,7401
Non-polymers4411
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: Heat shock protein HSP 90-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,1802
Polymers26,7401
Non-polymers4411
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
E: Heat shock protein HSP 90-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,1802
Polymers26,7401
Non-polymers4411
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
G: Heat shock protein HSP 90-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,1802
Polymers26,7401
Non-polymers4411
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)55.400, 95.210, 102.360
Angle α, β, γ (deg.)90.000, 91.300, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein
Heat shock protein HSP 90-alpha / Heat shock response / 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: 26739.922 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSP90AA1, HSP90A, HSPC1, HSPCA / Plasmid: pRSET A / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P07900
#2: Chemical
ChemComp-9J0 / 3-methyl-4-{4-[4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzamide


Mass: 440.500 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C24H24N8O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 102 / 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: 2.52 Å3/Da / Density % sol: 55.68 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5 / Details: PEG 6000, 200mM NaCl, 50mM Tris pH 7.5

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Data collection

DiffractionMean temperature: 105 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Mar 25, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.5→102.334 Å / Num. all: 35809 / Num. obs: 35809 / % possible obs: 97.4 % / Redundancy: 3.7 % / Rpim(I) all: 0.024 / Rrim(I) all: 0.047 / Rsym value: 0.04 / Net I/av σ(I): 16.1 / Net I/σ(I): 20.5 / Num. measured all: 131060
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsRpim(I) allRrim(I) allRsym value% possible all
2.5-2.643.50.233.251090.1420.2710.2395.8
2.64-2.83.60.1534.848690.0930.180.15396.6
2.8-2.993.70.1176.246260.0710.1370.11797
2.99-3.233.70.0779.343130.0470.090.07797.3
3.23-3.543.70.05213.139860.0320.0610.05297.7
3.54-3.953.70.03419.236470.0210.040.03498.1
3.95-4.563.70.0232.932080.0120.0230.0298.4
4.56-5.593.70.01931.327350.0120.0230.01998.5
5.59-7.913.70.02129.521370.0130.0250.02198.9
7.91-43.1633.60.01435.111790.0090.0170.01498

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Phasing

PhasingMethod: molecular replacement
Phasing MRR rigid body: 0.331
Highest resolutionLowest resolution
Rotation43.17 Å2.76 Å

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
SCALA3.3.22data scaling
MOLREPphasing
REFMAC5.8.0158refinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3WQ9
Resolution: 2.5→102.33 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.909 / SU B: 11.245 / SU ML: 0.241 / SU R Cruickshank DPI: 0.5322 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.532 / ESU R Free: 0.293
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2535 1956 5.5 %RANDOM
Rwork0.2023 ---
obs0.2053 33829 97.07 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 92.37 Å2 / Biso mean: 41.547 Å2 / Biso min: 15.45 Å2
Baniso -1Baniso -2Baniso -3
1--0.01 Å2-0 Å20.01 Å2
2--0.01 Å20 Å2
3----0 Å2
Refinement stepCycle: final / Resolution: 2.5→102.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6591 0 132 102 6825
Biso mean--32.37 33.22 -
Num. residues----848
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0196842
X-RAY DIFFRACTIONr_bond_other_d0.0060.026337
X-RAY DIFFRACTIONr_angle_refined_deg1.9611.9879258
X-RAY DIFFRACTIONr_angle_other_deg1.031314685
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.5525844
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.55825.253297
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.339151213
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.5811527
X-RAY DIFFRACTIONr_chiral_restr0.0890.21052
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.027588
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021351
LS refinement shellResolution: 2.5→2.565 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.299 113 -
Rwork0.284 2463 -
all-2576 -
obs--95.09 %

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