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- PDB-5fnd: Dynamic Undocking and the Quasi-Bound State as tools for Drug Design -

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Basic information

Entry
Database: PDB / ID: 5fnd
TitleDynamic Undocking and the Quasi-Bound State as tools for Drug Design
ComponentsHEAT SHOCK PROTEIN, HSP90-ALPHA
KeywordsCHAPERONE / HSP90 / DRUG DESIGN / ONCOLOGY
Function / homology
Function and homology information


sperm mitochondrial sheath / sulfonylurea receptor binding / dATP binding / CTP binding / positive regulation of protein polymerization / vRNP Assembly / Scavenging by Class F Receptors / UTP binding / sperm plasma membrane / chaperone-mediated autophagy ...sperm mitochondrial sheath / sulfonylurea receptor binding / dATP binding / CTP binding / positive regulation of protein polymerization / vRNP Assembly / Scavenging by Class F Receptors / UTP binding / sperm plasma membrane / chaperone-mediated autophagy / Rho GDP-dissociation inhibitor binding / Respiratory syncytial virus genome replication / telomerase holoenzyme complex assembly / mitochondrial transport / Uptake and function of diphtheria toxin / protein insertion into mitochondrial outer membrane / 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 / TPR domain binding / PIWI-interacting RNA (piRNA) biogenesis / Assembly and release of respiratory syncytial virus (RSV) virions / non-chaperonin molecular chaperone ATPase / dendritic growth cone / Sema3A PAK dependent Axon repulsion / protein unfolding / positive regulation of cell size / regulation of protein ubiquitination / HSF1-dependent transactivation / response to unfolded protein / enzyme-substrate adaptor activity / skeletal muscle contraction / regulation of postsynaptic membrane neurotransmitter receptor levels / regulation of protein-containing complex assembly / HSF1 activation / telomere maintenance via telomerase / Attenuation phase / chaperone-mediated protein complex assembly / neurofibrillary tangle assembly / axonal growth cone / RHOBTB2 GTPase cycle / positive regulation of lamellipodium assembly / eNOS activation / nitric oxide metabolic process / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / DNA polymerase binding / positive regulation of defense response to virus by host / response to salt stress / Signaling by ERBB2 / cardiac muscle cell apoptotic process / positive regulation of telomere maintenance via telomerase / 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 / nitric-oxide synthase regulator activity / 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 / positive regulation of interferon-beta production / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / response to cold / ESR-mediated signaling / Constitutive Signaling by Overexpressed ERBB2 / protein tyrosine kinase binding / AURKA Activation by TPX2 / VEGFR2 mediated vascular permeability / ATP-dependent protein folding chaperone / response to cocaine / Signaling by ERBB2 TMD/JMD mutants / brush border membrane / Constitutive Signaling by EGFRvIII / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / DDX58/IFIH1-mediated induction of interferon-alpha/beta / cellular response to virus / Regulation of actin dynamics for phagocytic cup formation / Regulation of necroptotic cell death / tau protein binding / VEGFA-VEGFR2 Pathway / histone deacetylase binding / positive regulation of protein import into nucleus / Downregulation of ERBB2 signaling / response to estrogen / Chaperone Mediated Autophagy / positive regulation of protein catabolic process / neuron migration / Aggrephagy / disordered domain specific binding / MHC class II protein complex binding / The role of GTSE1 in G2/M progression after G2 checkpoint
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-like ATPase, C-terminal domain / Heat Shock Protein 90 / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / 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-like ATPase, C-terminal domain / Heat Shock Protein 90 / Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase / 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-IQ5 / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsRuiz-Carmona, S. / Schmidtke, P. / Luque, F.J. / Baker, L.M. / Matassova, N. / Davis, B. / Roughley, S. / Murray, J. / Hubbard, R. / Barril, X.
CitationJournal: Nat Chem / Year: 2017
Title: Dynamic undocking and the quasi-bound state as tools for drug discovery.
Authors: Ruiz-Carmona, S. / Schmidtke, P. / Luque, F.J. / Baker, L. / Matassova, N. / Davis, B. / Roughley, S. / Murray, J. / Hubbard, R. / Barril, X.
History
DepositionNov 13, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 23, 2016Provider: repository / Type: Initial release
Revision 1.1Mar 8, 2017Group: Database references
Revision 1.2Nov 6, 2019Group: Data collection / Other / Category: diffrn_detector / pdbx_database_status
Item: _diffrn_detector.detector / _pdbx_database_status.status_code_sf
Revision 1.3Jan 10, 2024Group: 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

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Assembly

Deposited unit
A: HEAT SHOCK PROTEIN, HSP90-ALPHA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)27,0154
Polymers26,6021
Non-polymers4133
Water3,585199
1
A: HEAT SHOCK PROTEIN, HSP90-ALPHA
hetero molecules

A: HEAT SHOCK PROTEIN, HSP90-ALPHA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,0308
Polymers53,2042
Non-polymers8276
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_655-x+1,-y,z1
Buried area2510 Å2
ΔGint-73.3 kcal/mol
Surface area18280 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.960, 88.412, 99.059
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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Components

#1: Protein HEAT SHOCK PROTEIN, HSP90-ALPHA / HEAT SHOCK 86 KDA / HSP 86 / HSP86 / HEAT SHOCK PROTEIN / LIPOPOLYSACCHARIDE-ASSOCIATED PROTEIN 2 / ...HEAT SHOCK 86 KDA / HSP 86 / HSP86 / HEAT SHOCK PROTEIN / LIPOPOLYSACCHARIDE-ASSOCIATED PROTEIN 2 / LAP-2 / LPS-ASSOCIATED PROTEIN 2 / RENAL CARCINOMA ANTIGEN NY-REN-38 / HSP90-ALPHA


Mass: 26601.773 Da / Num. of mol.: 1 / Fragment: N-TERMINAL ATP-BINDING DOMAIN, RESIDUES 1-236
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Tissue: MELANOMA / Organ: SKIN / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P07900
#2: Chemical ChemComp-IQ5 / N-(2-AZANYL-6-METHYL-1,3-BENZOTHIAZOL-5-YL)ETHANAMIDE


Mass: 221.279 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H11N3OS
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 199 / 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: 2.67 Å3/Da / Density % sol: 53.99 % / Description: NONE
Crystal growpH: 6.5 / Details: pH 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: BRUKER D8 VENTURE TXS GENERATOR / Wavelength: 1.5418
DetectorType: BRUKER PHOTON 100 / Detector: CMOS / Date: Oct 28, 2014 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→65.97 Å / Num. obs: 19011 / % possible obs: 96.7 % / Observed criterion σ(I): 1 / Redundancy: 3.01 % / Rmerge(I) obs: 0.05 / Net I/σ(I): 11.1
Reflection shellResolution: 2→2.1 Å / Redundancy: 2 % / Rmerge(I) obs: 0.41 / Mean I/σ(I) obs: 1.34 / % possible all: 90.9

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Processing

Software
NameVersionClassification
REFMAC5.7.0029refinement
SAINTdata reduction
SADABSdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2WI6

2wi6


Resolution: 2→21.32 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.907 / SU B: 5.536 / SU ML: 0.145 / Cross valid method: THROUGHOUT / ESU R: 0.191 / ESU R Free: 0.203 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.30777 975 5.1 %RANDOM
Rwork0.22145 ---
obs0.22548 18035 96.69 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 31.828 Å2
Baniso -1Baniso -2Baniso -3
1--0.83 Å20 Å20 Å2
2--1.7 Å20 Å2
3----0.88 Å2
Refinement stepCycle: LAST / Resolution: 2→21.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1625 0 25 199 1849
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0191682
X-RAY DIFFRACTIONr_bond_other_d0.0010.021611
X-RAY DIFFRACTIONr_angle_refined_deg1.9581.9792275
X-RAY DIFFRACTIONr_angle_other_deg0.9253.0033711
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6895209
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.57725.06873
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.16115304
X-RAY DIFFRACTIONr_dihedral_angle_4_deg24.183157
X-RAY DIFFRACTIONr_chiral_restr0.1140.2262
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.021884
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02367
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
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: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.431 63 -
Rwork0.373 1237 -
obs--90.4 %

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