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- PDB-5t9u: Discovery of a Potent Cyclophilin Inhibitor (Compound 3) based on... -

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Basic information

Entry
Database: PDB / ID: 5t9u
TitleDiscovery of a Potent Cyclophilin Inhibitor (Compound 3) 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 / negative regulation of stress-activated MAPK cascade / endothelial cell activation ...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 / negative regulation of stress-activated MAPK cascade / endothelial cell activation / virion binding / 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 / 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 aggregation / platelet activation / SARS-CoV-1 activates/modulates innate immune responses / unfolded protein binding / integrin binding / protein folding / Platelet degranulation / cellular response to oxidative stress / positive regulation of NF-kappaB transcription factor activity / secretory granule lumen / vesicle / ficolin-1-rich granule lumen / positive regulation of MAPK cascade / positive regulation of protein phosphorylation / focal adhesion / apoptotic process / Neutrophil degranulation / protein-containing complex / extracellular space / RNA binding / 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]-10,12-dimethoxy-9,11-dimethyl-6-(propan-2-yl)-19-oxa-1,4,7,25-tetraazabicyclo[19.3.1]pentacosa-13,15-diene-2,5,8,20-tetrone / Chem-7HG / Peptidyl-prolyl cis-trans isomerase A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 2.301 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 1, 2017Group: Other
Revision 1.2Feb 8, 2017Group: Database references
Revision 1.3Feb 15, 2017Group: Database references
Revision 1.4Mar 29, 2017Group: Structure summary
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

Downloads & links

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Assembly

Deposited unit
A: Peptidyl-prolyl cis-trans isomerase A
B: Peptidyl-prolyl cis-trans isomerase A
C: Peptidyl-prolyl cis-trans isomerase A
D: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,2018
Polymers71,6304
Non-polymers2,5714
Water11,313628
1
A: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,5502
Polymers17,9071
Non-polymers6431
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,5502
Polymers17,9071
Non-polymers6431
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,5502
Polymers17,9071
Non-polymers6431
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Peptidyl-prolyl cis-trans isomerase A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,5502
Polymers17,9071
Non-polymers6431
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)137.973, 137.973, 125.786
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number154
Space group name H-MP3221

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Components

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


Mass: 17907.389 Da / Num. of mol.: 4
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-7HG / 3-[(3-hydroxyphenyl)methyl]-10,12-dimethoxy-9,11-dimethyl-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: 642.783 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C34H50N4O8
References: 3-[(3-hydroxyphenyl)methyl]-10,12-dimethoxy-9,11-dimethyl-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 / Water


Mass: 18.015 Da / Num. of mol.: 628 / 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: 4.83 Å3/Da / Density % sol: 74.51 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 8.5
Details: 0.1 M Tris-HCl, pH 8.5 0.1 M potassium chloride 2.2 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→45.162 Å / Num. obs: 61531 / % possible obs: 99.9 % / Redundancy: 4.49 % / Rmerge(I) obs: 0.043 / Net I/σ(I): 20.7
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*TREK9.7 W8RSSIdata scaling
PHENIX1.9_1692refinement
PDB_EXTRACT3.2data extraction
RefinementResolution: 2.301→45.162 Å / SU ML: 0.21 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 19.43
RfactorNum. reflection% reflection
Rfree0.1925 1978 3.21 %
Rwork0.1654 --
obs0.1663 61531 99.85 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 93.79 Å2 / Biso mean: 31.7922 Å2 / Biso min: 14.13 Å2
Refinement stepCycle: final / Resolution: 2.301→45.162 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5000 0 184 628 5812
Biso mean--29.72 39.49 -
Num. residues----653
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0095360
X-RAY DIFFRACTIONf_angle_d1.1467202
X-RAY DIFFRACTIONf_chiral_restr0.048741
X-RAY DIFFRACTIONf_plane_restr0.005937
X-RAY DIFFRACTIONf_dihedral_angle_d12.6881876
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 (%)
2.3011-2.35860.25221380.21684163430199
2.3586-2.42240.2671410.217642624403100
2.4224-2.49370.24361400.20741844324100
2.4937-2.57410.21471390.192542134352100
2.5741-2.66610.26451430.201542324375100
2.6661-2.77290.25231420.195142264368100
2.7729-2.8990.20261390.187842324371100
2.899-3.05190.20481410.195342474388100
3.0519-3.2430.21411400.186542244364100
3.243-3.49330.21231390.160142564395100
3.4933-3.84470.16881420.150142694411100
3.8447-4.40060.16171440.127742754419100
4.4006-5.54270.14021440.123343414485100
5.5427-45.17090.15741460.15874429457599

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