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

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Basic information

Entry
Database: PDB / ID: 5fnc
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


sulfonylurea receptor binding / sperm mitochondrial sheath / dATP binding / CTP binding / positive regulation of protein polymerization / Scavenging by Class F Receptors / vRNP Assembly / UTP binding / sperm plasma membrane / chaperone-mediated autophagy ...sulfonylurea receptor binding / sperm mitochondrial sheath / dATP binding / CTP binding / positive regulation of protein polymerization / Scavenging by Class F Receptors / vRNP Assembly / 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 / dendritic growth cone / Assembly and release of respiratory syncytial virus (RSV) virions / PIWI-interacting RNA (piRNA) biogenesis / non-chaperonin molecular chaperone ATPase / Sema3A PAK dependent Axon repulsion / protein unfolding / regulation of protein ubiquitination / positive regulation of cell size / HSF1-dependent transactivation / response to unfolded protein / enzyme-substrate adaptor activity / skeletal muscle contraction / HSF1 activation / regulation of protein-containing complex assembly / telomere maintenance via telomerase / Attenuation phase / chaperone-mediated protein complex assembly / regulation of postsynaptic membrane neurotransmitter receptor levels / 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 / positive regulation of telomere maintenance via telomerase / 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 / activation of innate immune response / lysosomal lumen / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / positive regulation of interferon-beta production / nitric-oxide synthase regulator activity / protein tyrosine kinase binding / response to cold / ESR-mediated signaling / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / Constitutive Signaling by Overexpressed ERBB2 / AURKA Activation by TPX2 / VEGFR2 mediated vascular permeability / DDX58/IFIH1-mediated induction of interferon-alpha/beta / response to cocaine / brush border membrane / ATP-dependent protein folding chaperone / Regulation of necroptotic cell death / Signaling by ERBB2 TMD/JMD mutants / Constitutive Signaling by EGFRvIII / Downregulation of ERBB2 signaling / Signaling by ERBB2 ECD mutants / Signaling by ERBB2 KD Mutants / Chaperone Mediated Autophagy / Regulation of actin dynamics for phagocytic cup formation / cellular response to virus / tau protein binding / Aggrephagy / positive regulation of protein import into nucleus / VEGFA-VEGFR2 Pathway / response to estrogen / histone deacetylase binding / The role of GTSE1 in G2/M progression after G2 checkpoint / neuron migration / Regulation of PLK1 Activity at G2/M Transition / positive regulation of protein catabolic process / positive regulation of nitric oxide biosynthetic process
Similarity search - Function
Histidine kinase/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/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 superfamily / Ribosomal protein S5 domain 2-type fold / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-IEE / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.2 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)27,1395
Polymers26,6021
Non-polymers5374
Water3,009167
1
A: HEAT SHOCK PROTEIN, HSP90-ALPHA
hetero molecules

A: HEAT SHOCK PROTEIN, HSP90-ALPHA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)54,27710
Polymers53,2042
Non-polymers1,0748
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,-y,z1
Buried area2620 Å2
ΔGint-87.1 kcal/mol
Surface area18900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.872, 90.285, 98.332
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11A-1226-

SO4

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Components

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


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-IEE / 6-CHLORO-4-N-[(4-METHYLPHENYL)METHYL]PYRIMIDINE- 2,4-DIAMINE


Mass: 248.711 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H13ClN4
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 167 / 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: 2.79 Å3/Da / Density % sol: 55.91 % / 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: Dec 8, 2014 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.2→66.51 Å / Num. obs: 15401 / % possible obs: 99.5 % / Observed criterion σ(I): 2 / Redundancy: 4.27 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 11.17
Reflection shellResolution: 2.2→2.24 Å / Redundancy: 2.94 % / Rmerge(I) obs: 0.32 / Mean I/σ(I) obs: 2.94 / % possible all: 96.3

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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: 2.2→20.52 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.93 / SU B: 4.679 / SU ML: 0.119 / Cross valid method: THROUGHOUT / ESU R: 0.214 / ESU R Free: 0.19 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.24039 767 5 %RANDOM
Rwork0.19118 ---
obs0.19358 14634 99.46 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 26.659 Å2
Baniso -1Baniso -2Baniso -3
1-0.02 Å20 Å20 Å2
2--0.17 Å20 Å2
3----0.18 Å2
Refinement stepCycle: LAST / Resolution: 2.2→20.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1628 0 32 167 1827
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0191685
X-RAY DIFFRACTIONr_bond_other_d0.0010.021611
X-RAY DIFFRACTIONr_angle_refined_deg1.921.9832276
X-RAY DIFFRACTIONr_angle_other_deg0.8853.0033711
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8165207
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.57125.06873
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.8915304
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.05157
X-RAY DIFFRACTIONr_chiral_restr0.1130.2262
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.021880
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02369
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→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.318 52 -
Rwork0.233 1048 -
obs--97.35 %

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