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- PDB-3hhu: Human heat-shock protein 90 (HSP90) in complex with {4-[3-(2,4-di... -

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Basic information

Entry
Database: PDB / ID: 3hhu
TitleHuman heat-shock protein 90 (HSP90) in complex with {4-[3-(2,4-dihydroxy-5-isopropyl-phenyl)-5-thioxo- 1,5-dihydro-[1,2,4]triazol-4-yl]-benzyl}-carbamic acid ethyl ester {ZK 2819}
ComponentsHeat shock protein HSP 90-alphaHeat shock response
KeywordsCHAPERONE / HSP90 / ATPASE / ATP-BINDING / HEAT SHOCK / NUCLEOTIDE-BINDING / PHOSPHORYLATION / Alternative splicing / Cytoplasm / Phosphoprotein / Stress response
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 / protein insertion into mitochondrial outer membrane / chaperone-mediated autophagy / telomerase holoenzyme complex assembly / 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 / regulation of postsynaptic membrane neurotransmitter receptor levels / dendritic growth cone / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / skeletal muscle contraction / positive regulation of cell size / HSF1-dependent transactivation / telomere maintenance via telomerase / response to unfolded protein / chaperone-mediated protein complex assembly / protein unfolding / HSF1 activation / regulation of protein-containing complex assembly / Attenuation phase / RHOBTB2 GTPase cycle / positive regulation of lamellipodium assembly / eNOS activation / axonal growth cone / 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 / positive regulation of cardiac muscle contraction / Recruitment of mitotic centrosome proteins and complexes / cardiac muscle cell apoptotic process / positive regulation of telomerase activity / Signaling by ERBB2 / positive regulation of defense response to virus by host / endocytic vesicle lumen / response to salt stress / 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 / activation of innate immune response / nitric-oxide synthase regulator activity / response to cold / positive regulation of interferon-beta production / lysosomal lumen / Constitutive Signaling by Overexpressed ERBB2 / AURKA Activation by TPX2 / 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 / Constitutive Signaling by EGFRvIII / DDX58/IFIH1-mediated induction of interferon-alpha/beta / 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 / positive regulation of nitric oxide biosynthetic process / Regulation of PLK1 Activity at G2/M Transition / disordered domain specific binding / 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-819 / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 1.59 Å
AuthorsAdler, M. / Whitlow, M.
CitationJournal: Chem.Biol.Drug Des. / Year: 2009
Title: Potent triazolothione inhibitor of heat-shock protein-90.
Authors: Feldman, R.I. / Mintzer, B. / Zhu, D. / Wu, J.M. / Biroc, S.L. / Yuan, S. / Emayan, K. / Chang, Z. / Chen, D. / Arnaiz, D.O. / Bryant, J. / Ge, X.S. / Whitlow, M. / Adler, M. / Polokoff, M.A. ...Authors: Feldman, R.I. / Mintzer, B. / Zhu, D. / Wu, J.M. / Biroc, S.L. / Yuan, S. / Emayan, K. / Chang, Z. / Chen, D. / Arnaiz, D.O. / Bryant, J. / Ge, X.S. / Whitlow, M. / Adler, M. / Polokoff, M.A. / Li, W.W. / Ferrer, M. / Sato, T. / Gu, J.M. / Shen, J. / Tseng, J.L. / Dinter, H. / Buckman, B.
History
DepositionMay 17, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 14, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 1, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.3Feb 21, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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

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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)51,2504
Polymers50,3932
Non-polymers8572
Water10,160564
1
A: Heat shock protein HSP 90-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,6252
Polymers25,1961
Non-polymers4291
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Heat shock protein HSP 90-alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,6252
Polymers25,1961
Non-polymers4291
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)65.019, 90.036, 100.040
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein Heat shock protein HSP 90-alpha / Heat shock response / HSP 86 / Renal carcinoma antigen NY-REN-38


Mass: 25196.393 Da / Num. of mol.: 2 / Fragment: UNP residues 1-224 / Source method: isolated from a natural source
Details: purified N-terminal domain of Hsp90, CRELUX GmbH (Martinsried Germany)
Source: (natural) Homo sapiens (human) / References: UniProt: P07900
#2: Chemical ChemComp-819 / ethyl (4-{3-[2,4-dihydroxy-5-(1-methylethyl)phenyl]-5-sulfanyl-4H-1,2,4-triazol-4-yl}benzyl)carbamate


Mass: 428.505 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H24N4O4S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 564 / 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: 2.91 Å3/Da / Density % sol: 57.66 %
Crystal growTemperature: 278 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 0.2 M MgCl, 30% PEG4000,0.1M Tris, pH 8.5, VAPOR DIFFUSION, HANGING DROP, temperature 278K

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Data collection

DiffractionMean temperature: 101.400002 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Apr 5, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.59→50 Å / Num. all: 79614 / Num. obs: 79136 / % possible obs: 99.4 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.49 % / Biso Wilson estimate: 15.3 Å2 / Rsym value: 0.0953 / Net I/σ(I): 9.79
Reflection shellResolution: 1.59→1.69 Å / Redundancy: 3.58 % / Mean I/σ(I) obs: 1.69 / Rsym value: 0.3932 / % possible all: 99.9

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
SCALAdata scaling
CNSrefinement
PDB_EXTRACT3.005data extraction
BOSdata collection
X-GENdata reduction
X-GENdata scaling
MOLREPphasing
CCP4phasing
CNX2005refinement
RefinementMethod to determine structure: OTHER / Resolution: 1.59→19.89 Å / Rfactor Rfree error: 0.004 / Occupancy max: 1 / Occupancy min: 0.2 / FOM work R set: 0.862 / Data cutoff high absF: 140750 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 2 / Stereochemistry target values: Engh & Huber
Details: Atoms C1 to C8 in inhibitor ZK 7002819 in the first Hsp90 molecule, residues 500, have been replaced by those from a previous Xplor refinement cool_09C1.pdb.
RfactorNum. reflection% reflectionSelection details
Rfree0.225 2614 4 %RANDOM
Rwork0.203 ---
obs0.204 65188 81.8 %-
all-79085 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 50.048 Å2 / ksol: 0.326 e/Å3
Displacement parametersBiso max: 72.23 Å2 / Biso mean: 18.237 Å2 / Biso min: 4.08 Å2
Baniso -1Baniso -2Baniso -3
1--3.51 Å20 Å20 Å2
2--6.76 Å20 Å2
3----3.25 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.21 Å0.19 Å
Luzzati d res low-5 Å
Luzzati sigma a0.16 Å0.14 Å
Refinement stepCycle: LAST / Resolution: 1.59→19.89 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3280 0 60 564 3904
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.005
X-RAY DIFFRACTIONc_angle_deg0.8
X-RAY DIFFRACTIONc_dihedral_angle_d21.1
X-RAY DIFFRACTIONc_improper_angle_d0.66
X-RAY DIFFRACTIONc_mcbond_it1.412
X-RAY DIFFRACTIONc_mcangle_it1.982.5
X-RAY DIFFRACTIONc_scbond_it2.62.5
X-RAY DIFFRACTIONc_scangle_it3.713.5
LS refinement shellResolution: 1.59→1.69 Å / Rfactor Rfree error: 0.015 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.282 332 4.1 %
Rwork0.255 7848 -
all-8180 -
obs--62.7 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2water_rep.paramwater.top
X-RAY DIFFRACTION3ion.paramion.top
X-RAY DIFFRACTION4819.par819.top

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