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- PDB-5t9w: Discovery of a Potent Cyclophilin Inhibitor (Compound 5) based on... -

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Basic information

Entry
Database: PDB / ID: 5t9w
TitleDiscovery of a Potent Cyclophilin Inhibitor (Compound 5) 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
3-[(3-hydroxyphenyl)methyl]-6-(propan-2-yl)-19-oxa-1,4,7,25-tetraazabicyclo[19.3.1]pentacosa-13,15-diene-2,5,8,20-tetrone / Chem-78E / Peptidyl-prolyl cis-trans isomerase A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2 Å
AuthorsAppleby, T.C. / Steadman, V. / Pettit, P. / 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)18,4602
Polymers17,9051
Non-polymers5551
Water3,801211
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)64.864, 84.514, 68.533
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-565-

HOH

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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: Bacteria (eubacteria) / References: UniProt: P62937, peptidylprolyl isomerase
#2: Chemical ChemComp-78E / 3-[(3-hydroxyphenyl)methyl]-6-(propan-2-yl)-19-oxa-1,4,7,25-tetraazabicyclo[19.3.1]pentacosa-13,15-diene-2,5,8,20-tetrone


Type: peptide-like, Peptide-like / Class: Inhibitor / Mass: 554.678 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H42N4O6
References: 3-[(3-hydroxyphenyl)methyl]-6-(propan-2-yl)-19-oxa-1,4,7,25-tetraazabicyclo[19.3.1]pentacosa-13,15-diene-2,5,8,20-tetrone
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 211 / 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: 2.62 Å3/Da / Density % sol: 53.1 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 0.05 M monobasic potassium phosphate 20% (w/v) PEG 8000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.979 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: May 26, 2010
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 12725 / % possible obs: 97.2 % / Redundancy: 4.1 % / Rmerge(I) obs: 0.05 / Net I/av σ(I): 24.5 / Net I/σ(I): 12.7
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2-2.0640.124198.3
2.06-2.134.10.109199.6
2.13-2.24.10.089199.4
2.2-2.294.10.084199.3
2.29-2.3940.079199.1
2.39-2.524.10.077198.8
2.52-2.684.10.081198.1
2.68-2.884.10.075198
2.88-3.174.10.061196.9
3.17-3.6340.033195.7
3.63-4.584.20.028194.2
4.58-504.20.024189.6

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Processing

Software
NameVersionClassification
HKL-2000data collection
SCALEPACKdata scaling
PHENIX1.6.4_486refinement
PDB_EXTRACT3.2data extraction
RefinementResolution: 2→41.149 Å / SU ML: 0.18 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 16.81
RfactorNum. reflection% reflection
Rfree0.1841 1253 10 %
Rwork0.1508 --
obs0.1542 12530 95.75 %
Solvent computationShrinkage radii: 1.06 Å / VDW probe radii: 1.3 Å / Bsol: 33.552 Å2 / ksol: 0.336 e/Å3
Displacement parametersBiso max: 80.69 Å2 / Biso mean: 14.54 Å2 / Biso min: 4.41 Å2
Baniso -1Baniso -2Baniso -3
1--3.6826 Å20 Å20 Å2
2--1.7419 Å2-0 Å2
3---1.9407 Å2
Refinement stepCycle: final / Resolution: 2→41.149 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1258 0 40 211 1509
Biso mean--11.97 25.2 -
Num. residues----164
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0061328
X-RAY DIFFRACTIONf_angle_d1.0241780
X-RAY DIFFRACTIONf_chiral_restr0.077181
X-RAY DIFFRACTIONf_plane_restr0.004235
X-RAY DIFFRACTIONf_dihedral_angle_d11.515469
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 9

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.9997-2.07980.19861360.13381241137795
2.0798-2.17440.19791420.14161250139298
2.1744-2.2890.20211420.14151242138497
2.289-2.43240.22241360.16041260139697
2.4324-2.62020.20541400.1651261140197
2.6202-2.88390.1921390.17081255139497
2.8839-3.3010.20551400.16511255139596
3.301-4.15830.16361370.14461249138694
4.1583-41.15720.141410.13881264140591

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