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- PDB-5ta4: Discovery of a Potent Cyclophilin Inhibitor (Compound 8) based on... -

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Basic information

Entry
Database: PDB / ID: 5ta4
TitleDiscovery of a Potent Cyclophilin Inhibitor (Compound 8) 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 / regulation of apoptotic signaling pathway / negative regulation of viral life cycle / cell adhesion molecule production / lipid droplet organization / heparan sulfate binding / regulation of viral genome replication / virion binding / leukocyte chemotaxis / endothelial cell activation ...negative regulation of protein K48-linked ubiquitination / regulation of apoptotic signaling pathway / negative regulation of viral life cycle / cell adhesion molecule production / lipid droplet organization / heparan sulfate binding / regulation of viral genome replication / virion binding / leukocyte chemotaxis / endothelial cell activation / negative regulation of stress-activated MAPK cascade / Basigin interactions / 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 / viral release from host cell / protein peptidyl-prolyl isomerization / Calcineurin activates NFAT / Binding and entry of HIV virion / positive regulation of viral genome replication / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / : / neutrophil chemotaxis / activation of protein kinase B activity / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / negative regulation of protein phosphorylation / peptidylprolyl isomerase / positive regulation of protein secretion / peptidyl-prolyl cis-trans isomerase activity / negative regulation of protein kinase activity / Assembly Of The HIV Virion / Budding and maturation of HIV virion / platelet activation / neuron differentiation / 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 / positive regulation of protein phosphorylation / focal adhesion / Neutrophil degranulation / apoptotic process / protein-containing complex / RNA binding / extracellular space / extracellular exosome / extracellular region / membrane / nucleus / cytosol / cytoplasm
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
18-methoxy-2,11,17-trimethyl-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-838 / Peptidyl-prolyl cis-trans isomerase A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 1.5 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 1.4Nov 22, 2017Group: Refinement description / Category: software
Revision 1.5Mar 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)18,5583
Polymers17,9051
Non-polymers6532
Water3,027168
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)47.797, 47.797, 64.504
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number78
Space group name H-MP43

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Components

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


Mass: 17905.307 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-838 / 18-methoxy-2,11,17-trimethyl-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


Class: Inhibitor / Mass: 556.694 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H44N4O6
References: 18-methoxy-2,11,17-trimethyl-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: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 168 / 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: 2.06 Å3/Da / Density % sol: 40.22 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 8.5
Details: 0.1 M Tris-HCl, pH 8.5 0.2 M potassium chloride 2.0 M ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Mar 7, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.5→19.2 Å / Num. obs: 23259 / % possible obs: 99.9 % / Redundancy: 4.49 % / Biso Wilson estimate: 14.95 Å2 / Rmerge(I) obs: 0.043 / Rrim(I) all: 0.043 / Χ2: 0.97 / Net I/σ(I): 20.7 / Num. measured all: 105166 / Scaling rejects: 789
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
1.5-1.554.130.4452.1199.3
1.55-1.614.280.2084.51100
1.61-1.694.390.1486.31100
1.69-1.784.430.1138.41100
1.78-1.894.510.07412.91100
1.89-2.034.530.05517.91100
2.03-2.244.620.04623.81100
2.24-2.564.670.0426.61100
2.56-3.224.70.03536.1199.8
3.22-19.24.60.02862.4199.6

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Processing

Software
NameVersionClassification
d*TREKdata scaling
PHENIX1.9_1692refinement
PDB_EXTRACT3.2data extraction
RefinementResolution: 1.5→19.2 Å / SU ML: 0.19 / Cross valid method: FREE R-VALUE / σ(F): 0.08 / Phase error: 22.58
RfactorNum. reflection% reflection
Rfree0.2062 1989 8.57 %
Rwork0.1759 --
obs0.1785 23203 99.63 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 72.47 Å2 / Biso mean: 15.416 Å2 / Biso min: 5.59 Å2
Refinement stepCycle: final / Resolution: 1.5→19.2 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1258 0 45 168 1471
Biso mean--16.03 25.7 -
Num. residues----164
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0071336
X-RAY DIFFRACTIONf_angle_d1.1211796
X-RAY DIFFRACTIONf_chiral_restr0.048185
X-RAY DIFFRACTIONf_plane_restr0.004236
X-RAY DIFFRACTIONf_dihedral_angle_d11.715478
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 (%)
1.499-1.53650.46371400.52921483162398
1.5365-1.5780.35881430.31411495163899
1.578-1.62440.2781370.249714931630100
1.6244-1.67680.24711420.209515101652100
1.6768-1.73670.21421450.191315251670100
1.7367-1.80620.21091440.172915011645100
1.8062-1.88840.18311410.164615181659100
1.8884-1.98780.20041380.171115431681100
1.9878-2.11220.2071430.162715061649100
2.1122-2.27510.18991450.160115231668100
2.2751-2.50360.20471410.16615321673100
2.5036-2.86480.23851420.184815061648100
2.8648-3.60540.18851440.161815291673100
3.6054-19.20310.16271440.14391550169499

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