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- PDB-5h22: Hsp90 alpha N-terminal domain in complex with an inhibitor -

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Basic information

Entry
Database: PDB / ID: 5h22
TitleHsp90 alpha N-terminal domain in complex with an inhibitor
ComponentsHsp90aa1 proteinHeat shock protein 90kDa alpha (cytosolic), member A1
KeywordsCHAPERONE/INHIBITOR / HSP90 / inhibitor / CHAPERONE-INHIBITOR complex
Function / homology
Function and homology information


Drug-mediated inhibition of ERBB2 signaling / ESR-mediated signaling / DDX58/IFIH1-mediated induction of interferon-alpha/beta / HSF1-dependent transactivation / Signaling by ERBB2 / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / eNOS activation / HSF1 activation / RHOBTB2 GTPase cycle / Sema3A PAK dependent Axon repulsion ...Drug-mediated inhibition of ERBB2 signaling / ESR-mediated signaling / DDX58/IFIH1-mediated induction of interferon-alpha/beta / HSF1-dependent transactivation / Signaling by ERBB2 / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / eNOS activation / HSF1 activation / RHOBTB2 GTPase cycle / Sema3A PAK dependent Axon repulsion / Downregulation of ERBB2 signaling / Attenuation phase / Regulation of necroptotic cell death / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / VEGFR2 mediated vascular permeability / positive regulation of cytotoxic T cell differentiation / Extra-nuclear estrogen signaling / The role of GTSE1 in G2/M progression after G2 checkpoint / Loss of Nlp from mitotic centrosomes / Recruitment of mitotic centrosome proteins and complexes / Loss of proteins required for interphase microtubule organization from the centrosome / Regulation of actin dynamics for phagocytic cup formation / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / AURKA Activation by TPX2 / Regulation of PLK1 Activity at G2/M Transition / Estrogen-dependent gene expression / VEGFA-VEGFR2 Pathway / sperm mitochondrial sheath / dATP binding / sulfonylurea receptor binding / CTP binding / positive regulation of protein polymerization / UTP binding / sperm plasma membrane / protein insertion into mitochondrial outer membrane / telomerase holoenzyme complex assembly / Rho GDP-dissociation inhibitor binding / TPR domain binding / non-chaperonin molecular chaperone ATPase / regulation of postsynaptic membrane neurotransmitter receptor levels / dendritic growth cone / skeletal muscle contraction / regulation of protein ubiquitination / positive regulation of cell size / telomere maintenance via telomerase / response to unfolded protein / sperm flagellum / chaperone-mediated protein complex assembly / positive regulation of lamellipodium assembly / axonal growth cone / DNA polymerase binding / protein folding chaperone / positive regulation of cardiac muscle contraction / response to salt stress / cardiac muscle cell apoptotic process / positive regulation of defense response to virus by host / protein tyrosine kinase binding / nitric oxide biosynthetic process / response to cold / activation of innate immune response / Neutrophil degranulation / positive regulation of interferon-beta production / nitric-oxide synthase regulator activity / response to cocaine / brush border membrane / ATP-dependent protein folding chaperone / neuron migration / tau protein binding / cellular response to virus / positive regulation of protein import into nucleus / response to estrogen / histone deacetylase binding / positive regulation of protein catabolic process / regulation of protein localization / positive regulation of nitric oxide biosynthetic process / disordered domain specific binding / unfolded protein binding / melanosome / protein folding / myelin sheath / GTPase binding / cellular response to heat / response to heat / protein refolding / scaffold protein binding / basolateral plasma membrane / protein phosphatase binding / collagen-containing extracellular matrix / regulation of apoptotic process / transmembrane transporter binding / protein stabilization / response to xenobiotic stimulus / positive regulation of protein phosphorylation / apical plasma membrane / response to antibiotic / mRNA binding / neuronal cell body / ubiquitin protein ligase binding / GTP binding
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-7FT / Hsp90aa1 protein / Heat shock protein HSP 90-alpha
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.499 Å
AuthorsKim, E.E. / Shin, S.C. / Keum, G.C.
Funding support Korea, Republic Of, 1items
OrganizationGrant numberCountry
NRF 20110021713 Korea, Republic Of
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2017
Title: Synthesis and in vitro antiproliferative activity of C5-benzyl substituted 2-amino-pyrrolo[2,3-d]pyrimidines as potent Hsp90 inhibitors.
Authors: Lee, J.H. / Shin, S.C. / Seo, S.H. / Seo, Y.H. / Jeong, N. / Kim, C.W. / Kim, E.E. / Keum, G.
History
DepositionOct 13, 2016Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 11, 2017Provider: repository / Type: Initial release
Revision 1.1Apr 24, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 8, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Hsp90aa1 protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,5172
Polymers24,1091
Non-polymers4081
Water4,756264
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area10480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)66.787, 90.581, 98.943
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 Hsp90aa1 protein / Heat shock protein 90kDa alpha (cytosolic), member A1 / Heat shock protein HSP 90-alpha


Mass: 24109.275 Da / Num. of mol.: 1 / Fragment: UNP residues 10-224
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Hsp90aa1
Production host: Escherichia coli-Pichia pastoris shuttle vector pPpARG4 (others)
References: UniProt: A0PJ91, UniProt: P07901*PLUS
#2: Chemical ChemComp-7FT / 4-chloranyl-7-[(4-methoxy-3,5-dimethyl-pyridin-2-yl)methyl]-5-(phenylmethyl)pyrrolo[2,3-d]pyrimidin-2-amine


Mass: 407.896 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C22H22ClN5O
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 264 / 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: 3.2 Å3/Da / Density % sol: 61.59 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 8.5 / Details: 1.0M ammonium Sulfate, 0.1M Tris-HCl (pH8.5)

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: PAL/PLS / Beamline: 5C (4A) / Wavelength: 0.97951 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 27, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97951 Å / Relative weight: 1
ReflectionResolution: 1.499→50 Å / Num. obs: 48302 / % possible obs: 99.2 % / Redundancy: 7.6 % / Rmerge(I) obs: 0.076 / Net I/σ(I): 27.5
Reflection shellResolution: 1.5→1.55 Å / Rmerge(I) obs: 0.34

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155: ???)refinement
PDB_EXTRACT3.2data extraction
HKL-2000data processing
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1UY6

1uy6


Resolution: 1.499→29.87 Å / SU ML: 0.14 / Cross valid method: FREE R-VALUE / σ(F): 1.5 / Phase error: 19.32
RfactorNum. reflection% reflection
Rfree0.2077 2000 4.17 %
Rwork0.1941 --
obs0.1947 47908 99.01 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.499→29.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1672 0 0 264 1936
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0051701
X-RAY DIFFRACTIONf_angle_d0.8282296
X-RAY DIFFRACTIONf_dihedral_angle_d21.377625
X-RAY DIFFRACTIONf_chiral_restr0.078259
X-RAY DIFFRACTIONf_plane_restr0.004290
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4992-1.53670.28331350.2643100X-RAY DIFFRACTION96
1.5367-1.57820.23771410.2333239X-RAY DIFFRACTION99
1.5782-1.62470.26481430.22143266X-RAY DIFFRACTION99
1.6247-1.67710.22271410.20593247X-RAY DIFFRACTION99
1.6771-1.7370.19951420.19633254X-RAY DIFFRACTION99
1.737-1.80660.20341420.19493267X-RAY DIFFRACTION99
1.8066-1.88880.21661420.18993258X-RAY DIFFRACTION99
1.8888-1.98830.21661430.18123280X-RAY DIFFRACTION100
1.9883-2.11290.20311440.18793307X-RAY DIFFRACTION100
2.1129-2.2760.18631440.18773322X-RAY DIFFRACTION100
2.276-2.50490.21561440.1953304X-RAY DIFFRACTION100
2.5049-2.86710.22491450.21463321X-RAY DIFFRACTION100
2.8671-3.61130.21091470.1893370X-RAY DIFFRACTION100
3.6113-29.87620.18471470.18143373X-RAY DIFFRACTION97

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