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- PDB-4w7t: Crystal Structure of Hsp90-alpha N-domain Bound to the Inhibitor ... -

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Basic information

Entry
Database: PDB / ID: 4w7t
TitleCrystal Structure of Hsp90-alpha N-domain Bound to the Inhibitor NVP-HSP990
ComponentsHeat shock protein HSP 90-alpha
KeywordsCHAPERONE/INHIBITOR / ATP-binding domain / CHAPERONE-INHIBITOR complex
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 / Chaperone Mediated Autophagy / Aggrephagy / 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
Chem-3JC / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsBellamacina, C.R. / Shafer, C.M. / Bussiere, D.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Design, Structure-Activity Relationship, and in Vivo Characterization of the Development Candidate NVP-HSP990.
Authors: McBride, C.M. / Levine, B. / Xia, Y. / Bellamacina, C. / Machajewski, T. / Gao, Z. / Renhowe, P. / Antonios-McCrea, W. / Barsanti, P. / Brinner, K. / Costales, A. / Doughan, B. / Lin, X. / ...Authors: McBride, C.M. / Levine, B. / Xia, Y. / Bellamacina, C. / Machajewski, T. / Gao, Z. / Renhowe, P. / Antonios-McCrea, W. / Barsanti, P. / Brinner, K. / Costales, A. / Doughan, B. / Lin, X. / Louie, A. / McKenna, M. / Mendenhall, K. / Poon, D. / Rico, A. / Wang, M. / Williams, T.E. / Abrams, T. / Fong, S. / Hendrickson, T. / Lei, D. / Lin, J. / Menezes, D. / Pryer, N. / Taverna, P. / Xu, Y. / Zhou, Y. / Shafer, C.M.
History
DepositionAug 22, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 26, 2014Provider: repository / Type: Initial release
Revision 1.1Dec 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description / Source and taxonomy
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / entity_src_nat / pdbx_database_status / pdbx_prerelease_seq / pdbx_struct_oper_list / refine_hist
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity_src_nat.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_oper_list.symmetry_operation
Revision 1.2Apr 3, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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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)26,8552
Polymers26,6021
Non-polymers2531
Water6,521362
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area10110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.095, 89.983, 97.985
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222
Detailsbiological unit is the same as asym.

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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: 26601.773 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P07900
#2: Chemical ChemComp-3JC / (7S)-2-amino-4-methyl-7-phenyl-7,8-dihydroquinazolin-5(6H)-one


Mass: 253.299 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H15N3O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 362 / 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: 2.65 Å3/Da / Density % sol: 53.66 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: Protein is used at 12mg/ml crystallant is: 20% (w/v) PEG2K MME, 200 mM magnesium chloride, 100 mM sodium cacodylate Apo crystals are grown with equal volumes of protein to crystallant. ...Details: Protein is used at 12mg/ml crystallant is: 20% (w/v) PEG2K MME, 200 mM magnesium chloride, 100 mM sodium cacodylate Apo crystals are grown with equal volumes of protein to crystallant. Compound is dissolved to 200mM in equal volumes of EtOH:PEG400:DMI, then diluted into crystallant for a working stock of 4mM. 1ul of compound working stock is added to a drop containing Apo Hsp90 crystals. Soak for 3 days.
PH range: 6.5 / Temp details: room temperature

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Wavelength: 1.5418 Å
DetectorType: CUSTOM-MADE / Detector: AREA DETECTOR / Date: Mar 5, 2004 / Details: Burker Kappa CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.8→75 Å / Num. obs: 25722 / % possible obs: 96.7 % / Observed criterion σ(I): 2 / Redundancy: 4.5 % / Rmerge(I) obs: 0.052 / Rsym value: 0.052 / Net I/σ(I): 18.5
Reflection shellResolution: 1.8→1.86 Å / Redundancy: 2 % / Rmerge(I) obs: 0.5 / Mean I/σ(I) obs: 1.4 / % possible all: 74.4

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Processing

Software
NameVersionClassification
PHENIX(PHENIX.REFINE: DEV_572)refinement
EPMRphasing
PDB_EXTRACT3.14data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: HSP90 N-TERM DOMAIN 9-236

Resolution: 1.8→27.17 Å / SU ML: 0.2 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 18.47 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.21 1306 5.08 %Random selection
Rwork0.171 ---
obs0.173 25719 96.7 %-
Solvent computationShrinkage radii: 0.83 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 46.32 Å2 / ksol: 0.35 e/Å3
Displacement parametersBiso mean: 21.73 Å2
Baniso -1Baniso -2Baniso -3
1--1.7379 Å20 Å20 Å2
2---2.3832 Å20 Å2
3----0.2403 Å2
Refinement stepCycle: LAST / Resolution: 1.8→27.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1626 0 19 362 2007
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0041675
X-RAY DIFFRACTIONf_angle_d0.922262
X-RAY DIFFRACTIONf_dihedral_angle_d12.044614
X-RAY DIFFRACTIONf_chiral_restr0.064259
X-RAY DIFFRACTIONf_plane_restr0.003294
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.87220.30721190.29112049X-RAY DIFFRACTION75
1.8722-1.95740.24591400.21862622X-RAY DIFFRACTION95
1.9574-2.06060.24211380.17372793X-RAY DIFFRACTION100
2.0606-2.18960.18811520.15892770X-RAY DIFFRACTION100
2.1896-2.35860.19931550.16112774X-RAY DIFFRACTION100
2.3586-2.59580.21031570.16322792X-RAY DIFFRACTION100
2.5958-2.9710.18541550.1692801X-RAY DIFFRACTION100
2.971-3.74160.21991350.15682864X-RAY DIFFRACTION100
3.7416-27.16990.19771550.16592948X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: -1.7544 Å / Origin y: -14.3545 Å / Origin z: -20.3469 Å
111213212223313233
T0.0907 Å20.0041 Å2-0.0122 Å2-0.0736 Å2-0.003 Å2--0.0861 Å2
L0.8068 °2-0.0389 °2-0.1541 °2-0.6237 °20.1397 °2--0.5136 °2
S0.0279 Å °0.0124 Å °0.0401 Å °0.018 Å °0.0134 Å °-0.0081 Å °0.0035 Å °-0.0004 Å °-0.0155 Å °
Refinement TLS groupSelection details: CHAIN A

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