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- PDB-5t9z: Discovery of a Potent Cyclophilin Inhibitor (Compound 6) based on... -

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Basic information

Entry
Database: PDB / ID: 5t9z
TitleDiscovery of a Potent Cyclophilin Inhibitor (Compound 6) based on Structural Simplification of Sanglifehrin A
ComponentsPeptidyl-prolyl cis-trans isomerase A
Keywordsisomerase/isomerase inhibitor / cyclophilin inhibitor antiviral HCV / isomerase-isomerase inhibitor complex
Function / homology
Function and homology information


negative regulation of protein K48-linked ubiquitination / negative regulation of viral life cycle / regulation of apoptotic signaling pathway / cell adhesion molecule production / lipid droplet organization / heparan sulfate binding / regulation of viral genome replication / leukocyte chemotaxis / endothelial cell activation / virion binding ...negative regulation of protein K48-linked ubiquitination / negative regulation of viral life cycle / regulation of apoptotic signaling pathway / cell adhesion molecule production / lipid droplet organization / heparan sulfate binding / regulation of viral genome replication / leukocyte chemotaxis / endothelial cell activation / virion binding / Basigin interactions / negative regulation of stress-activated MAPK cascade / cyclosporin A binding / Minus-strand DNA synthesis / Plus-strand DNA synthesis / Uncoating of the HIV Virion / Early Phase of HIV Life Cycle / Integration of provirus / APOBEC3G mediated resistance to HIV-1 infection / Calcineurin activates NFAT / viral release from host cell / positive regulation of viral genome replication / Binding and entry of HIV virion / protein peptidyl-prolyl isomerization / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / positive regulation of protein dephosphorylation / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / activation of protein kinase B activity / neutrophil chemotaxis / negative regulation of protein phosphorylation / peptidylprolyl isomerase / peptidyl-prolyl cis-trans isomerase activity / positive regulation of protein secretion / Assembly Of The HIV Virion / negative regulation of protein kinase activity / Budding and maturation of HIV virion / neuron differentiation / platelet activation / platelet aggregation / SARS-CoV-1 activates/modulates innate immune responses / unfolded protein binding / integrin binding / protein folding / Platelet degranulation / positive regulation of NF-kappaB transcription factor activity / cellular response to oxidative stress / secretory granule lumen / vesicle / ficolin-1-rich granule lumen / positive regulation of MAPK cascade / response to hypoxia / positive regulation of protein phosphorylation / focal adhesion / apoptotic process / Neutrophil degranulation / protein-containing complex / RNA binding / extracellular space / extracellular exosome / extracellular region / membrane / nucleus / cytoplasm / cytosol
Similarity search - Function
Cyclophilin-like / Cyclophilin / Cyclophilin-type peptidyl-prolyl cis-trans isomerase / Cyclophilin-type peptidyl-prolyl cis-trans isomerase, conserved site / Cyclophilin-type peptidyl-prolyl cis-trans isomerase signature. / Cyclophilin-type peptidyl-prolyl cis-trans isomerase domain profile. / Cyclophilin-type peptidyl-prolyl cis-trans isomerase domain / Cyclophilin type peptidyl-prolyl cis-trans isomerase/CLD / Cyclophilin-like domain superfamily / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
11-[(3-hydroxyphenyl)methyl]-18-methoxy-17-methyl-14-(propan-2-yl)-3-oxa-9,12,15,28-tetraazatricyclo[21.3.1.1~5,9~]octacosa-1(27),21,23,25-tetraene-4,10,13,16-tetrone / Chem-78R / Peptidyl-prolyl cis-trans isomerase A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.4 Å
AuthorsAppleby, T.C. / Steadman, V. / Pettit, S. / Schmitz, U. / Mackman, R.L. / Schultz, B.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Discovery of Potent Cyclophilin Inhibitors Based on the Structural Simplification of Sanglifehrin A.
Authors: Steadman, V.A. / Pettit, S.B. / Poullennec, K.G. / Lazarides, L. / Keats, A.J. / Dean, D.K. / Stanway, S.J. / Austin, C.A. / Sanvoisin, J.A. / Watt, G.M. / Fliri, H.G. / Liclican, A.C. / ...Authors: Steadman, V.A. / Pettit, S.B. / Poullennec, K.G. / Lazarides, L. / Keats, A.J. / Dean, D.K. / Stanway, S.J. / Austin, C.A. / Sanvoisin, J.A. / Watt, G.M. / Fliri, H.G. / Liclican, A.C. / Jin, D. / Wong, M.H. / Leavitt, S.A. / Lee, Y.J. / Tian, Y. / Frey, C.R. / Appleby, T.C. / Schmitz, U. / Jansa, P. / Mackman, R.L. / Schultz, B.E.
History
DepositionSep 9, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 25, 2017Provider: repository / Type: Initial release
Revision 1.1Feb 8, 2017Group: Database references
Revision 1.2Feb 15, 2017Group: Database references
Revision 1.3Mar 29, 2017Group: Structure summary
Revision 1.4Mar 6, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,4112
Polymers17,7761
Non-polymers6351
Water3,747208
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)36.243, 51.865, 81.905
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Peptidyl-prolyl cis-trans isomerase A / PPIase A / Cyclophilin A / Cyclosporin A-binding protein / Rotamase A


Mass: 17776.193 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPIA, CYPA / Production host: Escherichia coli (E. coli) / References: UniProt: P62937, peptidylprolyl isomerase
#2: Chemical ChemComp-78R / 11-[(3-hydroxyphenyl)methyl]-18-methoxy-17-methyl-14-(propan-2-yl)-3-oxa-9,12,15,28-tetraazatricyclo[21.3.1.1~5,9~]octacosa-1(27),21,23,25-tetraene-4,10,13,16-tetrone


Type: peptide-like, Peptide-like / Class: Inhibitor / Mass: 634.762 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C35H46N4O7
References: 11-[(3-hydroxyphenyl)methyl]-18-methoxy-17-methyl-14-(propan-2-yl)-3-oxa-9,12,15,28-tetraazatricyclo[21.3.1.1~5,9~]octacosa-1(27),21,23,25-tetraene-4,10,13,16-tetrone
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 208 / 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: 2.17 Å3/Da / Density % sol: 43.19 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 4.2 / Details: sodium citrate, pH 4.2 25% (w/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jan 13, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.4→50 Å / Num. obs: 30819 / % possible obs: 98.8 % / Redundancy: 5.8 % / Rmerge(I) obs: 0.05 / Χ2: 0.868 / Net I/av σ(I): 30.611 / Net I/σ(I): 12.2 / Num. measured all: 179313
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
1.4-1.444.90.2620140.47992.7
1.44-1.475.70.23421430.51497.9
1.47-1.525.80.19321500.58897.7
1.52-1.5760.16121730.63599.1
1.57-1.6260.13321640.72499
1.62-1.6960.11421700.82598.8
1.69-1.7660.09921890.93499.1
1.76-1.8660.0822051.10299.4
1.86-1.9760.06522061.05199.5
1.97-2.1360.05422140.98799.7
2.13-2.3460.0522391.04399.6
2.34-2.685.90.05422411.08199.9
2.68-3.375.70.04122851.089100
3.37-505.60.03524260.92999.9

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Processing

Software
NameVersionClassification
HKL-2000data collection
SCALEPACKdata scaling
PHENIX1.9_1692refinement
PDB_EXTRACT3.2data extraction
RefinementResolution: 1.4→43.819 Å / SU ML: 0.12 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 17.79
RfactorNum. reflection% reflection
Rfree0.1901 1999 6.5 %
Rwork0.1628 --
obs0.1645 30763 98.66 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 77.91 Å2 / Biso mean: 15.126 Å2 / Biso min: 3.63 Å2
Refinement stepCycle: final / Resolution: 1.4→43.819 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1248 0 46 208 1502
Biso mean--13.19 25.34 -
Num. residues----163
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0151325
X-RAY DIFFRACTIONf_angle_d1.6051778
X-RAY DIFFRACTIONf_chiral_restr0.074182
X-RAY DIFFRACTIONf_plane_restr0.009232
X-RAY DIFFRACTIONf_dihedral_angle_d13.308515
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.3997-1.43470.22121290.1951856198591
1.4347-1.47350.24561380.1931998213698
1.4735-1.51690.23541400.16942017215798
1.5169-1.56580.20471410.172035217699
1.5658-1.62180.17641420.1642024216699
1.6218-1.68670.19011400.15982023216399
1.6867-1.76350.18371420.16342052219499
1.7635-1.85650.16231430.15722058220199
1.8565-1.97280.18261440.156720632207100
1.9728-2.12510.16271440.151220732217100
2.1251-2.33890.18091460.162620892235100
2.3389-2.67740.22081460.176320932239100
2.6774-3.3730.21891480.170621352283100
3.373-43.840.16721560.150922482404100

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