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- PDB-4awo: Complex of HSP90 ATPase domain with tropane derived inhibitors -

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Basic information

Entry
Database: PDB / ID: 4awo
TitleComplex of HSP90 ATPase domain with tropane derived inhibitors
ComponentsHEAT SHOCK PROTEIN HSP 90-ALPHA
KeywordsCHAPERONE
Function / homology
Function and homology information


sperm mitochondrial sheath / sulfonylurea receptor binding / dATP binding / CTP binding / positive regulation of protein polymerization / Scavenging by Class F Receptors / vRNP Assembly / UTP binding / chaperone-mediated autophagy / sperm plasma membrane ...sperm mitochondrial sheath / sulfonylurea receptor binding / dATP binding / CTP binding / positive regulation of protein polymerization / Scavenging by Class F Receptors / vRNP Assembly / UTP binding / chaperone-mediated autophagy / sperm plasma membrane / Respiratory syncytial virus genome replication / Rho GDP-dissociation inhibitor binding / telomerase holoenzyme complex assembly / 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 / Uptake and function of diphtheria toxin / protein import into mitochondrial matrix / TPR domain binding / dendritic growth cone / PIWI-interacting RNA (piRNA) biogenesis / Assembly and release of respiratory syncytial virus (RSV) virions / non-chaperonin molecular chaperone ATPase / protein unfolding / Sema3A PAK dependent Axon repulsion / regulation of protein ubiquitination / positive regulation of cell size / HSF1-dependent transactivation / protein folding chaperone complex / enzyme-substrate adaptor activity / response to unfolded protein / regulation of protein-containing complex assembly / HSF1 activation / Attenuation phase / chaperone-mediated protein complex assembly / neurofibrillary tangle assembly / RHOBTB2 GTPase cycle / regulation of postsynaptic membrane neurotransmitter receptor levels / telomere maintenance via telomerase / axonal growth cone / skeletal muscle contraction / positive regulation of lamellipodium assembly / nitric oxide metabolic process / positive regulation of defense response to virus by host / response to salt stress / eNOS activation / DNA polymerase binding / positive regulation of telomere maintenance via telomerase / Signaling by ERBB2 / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / cardiac muscle cell apoptotic process / endocytic vesicle lumen / positive regulation of cardiac muscle contraction / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / Recruitment of NuMA to mitotic centrosomes / activation of innate immune response / Anchoring of the basal body to the plasma membrane / lysosomal lumen / ESR-mediated signaling / positive regulation of interferon-beta production / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / Constitutive Signaling by Overexpressed ERBB2 / protein tyrosine kinase binding / response to cold / AURKA Activation by TPX2 / nitric-oxide synthase regulator activity / VEGFR2 mediated vascular permeability / response to cocaine / ATP-dependent protein folding chaperone / brush border membrane / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / positive regulation of protein import into nucleus / DDX58/IFIH1-mediated induction of interferon-alpha/beta / cellular response to virus / Regulation of actin dynamics for phagocytic cup formation / response to estrogen / Regulation of necroptotic cell death / VEGFA-VEGFR2 Pathway / extracellular matrix / tau protein binding / Downregulation of ERBB2 signaling / neuron migration / histone deacetylase binding / Chaperone Mediated Autophagy / disordered domain specific binding / positive regulation of nitric oxide biosynthetic process / Aggrephagy
Similarity search - Function
Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / Histidine kinase-like ATPase, C-terminal domain / HSP90, C-terminal domain / Heat shock protein Hsp90, N-terminal / Heat Shock Protein 90 / Heat shock protein Hsp90 family / Hsp90 protein / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase/HSP90-like ATPase ...Heat shock protein Hsp90, conserved site / Heat shock hsp90 proteins family signature. / Histidine kinase-like ATPase, C-terminal domain / HSP90, C-terminal domain / Heat shock protein Hsp90, N-terminal / Heat Shock Protein 90 / Heat shock protein Hsp90 family / Hsp90 protein / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase/HSP90-like ATPase / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / Histidine kinase-like ATPases / Histidine kinase/HSP90-like ATPase superfamily / Ribosomal protein S5 domain 2-type fold / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-99B / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsLougheed, J.C. / Stout, T.J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2012
Title: Discovery of Xl888: A Novel Tropane-Derived Small Molecule Inhibitor of Hsp90.
Authors: Bussenius, J. / Blazey, C.M. / Aay, N. / Anand, N.K. / Arcalas, A. / Baik, T. / Bowles, O.J. / Buhr, C.A. / Costanzo, S. / Curtis, J.K. / Defina, S.C. / Dubenko, L. / Heuer, T.S. / Huang, P. ...Authors: Bussenius, J. / Blazey, C.M. / Aay, N. / Anand, N.K. / Arcalas, A. / Baik, T. / Bowles, O.J. / Buhr, C.A. / Costanzo, S. / Curtis, J.K. / Defina, S.C. / Dubenko, L. / Heuer, T.S. / Huang, P. / Jaeger, C. / Joshi, A. / Kennedy, A.R. / Kim, A.I. / Lara, K. / Lee, J. / Li, J. / Lougheed, J.C. / Ma, S. / Malek, S. / Manalo, J.C. / Martini, J.F. / Mcgrath, G. / Nicoll, M. / Nuss, J.M. / Pack, M. / Peto, C.J. / Tsang, T.H. / Wang, L. / Womble, S.W. / Yakes, M. / Zhang, W. / Rice, K.D.
History
DepositionJun 5, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 29, 2012Provider: repository / Type: Initial release
Revision 1.1May 1, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / 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 / _pdbx_database_status.status_code_sf / _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)52,6094
Polymers51,6022
Non-polymers1,0072
Water4,900272
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1750 Å2
ΔGint-10.6 kcal/mol
Surface area18620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.656, 57.363, 57.442
Angle α, β, γ (deg.)70.87, 87.86, 68.95
Int Tables number1
Space group name H-MP1

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Components

#1: Protein HEAT SHOCK PROTEIN HSP 90-ALPHA / HSP90 / HEAT SHOCK 86 KDA / HSP 86 / HSP86 / RENAL CARCINOMA ANTIGEN NY-REN-38


Mass: 25800.898 Da / Num. of mol.: 2 / Fragment: ATPASE DOMAIN, RESIDUES 9-236
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli)
References: UniProt: P07900, non-chaperonin molecular chaperone ATPase
#2: Chemical ChemComp-99B / 5-[(2R)-butan-2-ylamino]-N-{(3-endo)-8-[5-(cyclopropylcarbonyl)pyridin-2-yl]-8-azabicyclo[3.2.1]oct-3-yl}-2-methylbenzene-1,4-dicarboxamide


Mass: 503.636 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H37N5O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 272 / 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: 2.58 Å3/Da / Density % sol: 51.92 % / Description: NONE
Crystal growpH: 8 / Details: pH 8.0

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Data collection

DiffractionMean temperature: 93.2 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.97946
DetectorType: MARRESEARCH / Detector: CCD / Date: Jul 5, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 1.7→41.51 Å / Num. obs: 52156 / % possible obs: 94.6 % / Observed criterion σ(I): -3 / Redundancy: 1.98 % / Rmerge(I) obs: 0.14 / Net I/σ(I): 11.6
Reflection shellResolution: 1.7→1.9 Å / Redundancy: 1.99 % / Rmerge(I) obs: 0.53 / Mean I/σ(I) obs: 1.69 / % possible all: 94.4

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: IN-HOUSE APO STRUCTURE

Resolution: 1.7→54.07 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.932 / SU B: 2.613 / SU ML: 0.088 / Cross valid method: THROUGHOUT / ESU R: 0.12 / ESU R Free: 0.119 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.25111 2628 5 %RANDOM
Rwork0.21303 ---
obs0.21504 49527 94.7 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 28.256 Å2
Baniso -1Baniso -2Baniso -3
1--0.37 Å20.69 Å20.95 Å2
2---0.52 Å2-0.27 Å2
3---0.49 Å2
Refinement stepCycle: LAST / Resolution: 1.7→54.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3233 0 74 272 3579
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0210.0223365
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.8751.9864543
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2335405
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.99525.135148
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.02415616
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.9241514
X-RAY DIFFRACTIONr_chiral_restr0.2210.2521
X-RAY DIFFRACTIONr_gen_planes_refined0.010.022472
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2110.21575
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3060.22308
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1330.2204
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2250.244
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1360.25
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.3281.52121
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.93523270
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.89531456
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it4.1384.51267
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.7→1.744 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.36 187 -
Rwork0.35 3654 -
obs--94.47 %

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