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- PDB-9ghy: Cyclophilin A in complex with Sanglifehrin A analogue (2R,3S,7S,1... -

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Basic information

Entry
Database: PDB / ID: 9ghy
TitleCyclophilin A in complex with Sanglifehrin A analogue (2R,3S,7S,10S,E)-10-(3-aminopropyl)-2,7-dimethylspiro[3,8,11-triaza-1(2,7)-quinolina-5(3,1)-pyridazinacyclopentadecaphanene-13,5'-[1,3]dioxan]-14-ene-4,6,9,12-tetraone
ComponentsPeptidyl-prolyl cis-trans isomerase A
KeywordsISOMERASE / Cyclophilin A / Sanglifehrin A / Inhibitor / Complex
Function / homology
Function and homology information


negative regulation of protein K48-linked ubiquitination / regulation of apoptotic signaling pathway / cell adhesion molecule production / negative regulation of viral life cycle / lipid droplet organization / heparan sulfate binding / regulation of viral genome replication / virion binding / leukocyte chemotaxis / negative regulation of stress-activated MAPK cascade ...negative regulation of protein K48-linked ubiquitination / regulation of apoptotic signaling pathway / cell adhesion molecule production / negative regulation of viral life cycle / lipid droplet organization / heparan sulfate binding / regulation of viral genome replication / virion binding / leukocyte chemotaxis / negative regulation of stress-activated MAPK cascade / endothelial cell activation / Basigin interactions / protein peptidyl-prolyl isomerization / 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 / negative regulation of protein phosphorylation / 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 / activation of protein kinase B activity / neutrophil chemotaxis / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / peptidyl-prolyl cis-trans isomerase activity / negative regulation of protein kinase activity / RNA polymerase II CTD heptapeptide repeat P3 isomerase activity / RNA polymerase II CTD heptapeptide repeat P6 isomerase activity / positive regulation of protein secretion / peptidylprolyl isomerase / Assembly Of The HIV Virion / Budding and maturation of HIV virion / platelet activation / platelet aggregation / neuron differentiation / positive regulation of NF-kappaB transcription factor activity / SARS-CoV-1 activates/modulates innate immune responses / integrin binding / unfolded protein binding / Platelet degranulation / protein folding / positive regulation of protein phosphorylation / cellular response to oxidative stress / secretory granule lumen / vesicle / ficolin-1-rich granule lumen / positive regulation of MAPK cascade / focal adhesion / apoptotic process / Neutrophil degranulation / protein-containing complex / extracellular space / RNA binding / extracellular exosome / extracellular region / nucleus / membrane / cytosol / cytoplasm
Similarity search - Function
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
Similarity search - Domain/homology
: / Peptidyl-prolyl cis-trans isomerase A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.15 Å
AuthorsMeyners, C. / Dreizler, J.K. / Hausch, F.
Funding support Germany, 2items
OrganizationGrant numberCountry
German Federal Ministry for Education and Research03ZU1109EB Germany
Hessian Ministry of Science, Higher Education and Art (HMWK) Germany
CitationJournal: Acs Med.Chem.Lett. / Year: 2024
Title: Toward Dual Targeting of Catalytic and Gatekeeper Pockets in Cyclophilins Using a Macrocyclic Scaffold.
Authors: Dreizler, J.K. / Meyners, C. / Hausch, F.
History
DepositionAug 16, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 6, 2024Provider: repository / Type: Initial release
Revision 1.1Dec 4, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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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)18,8753
Polymers18,2321
Non-polymers6432
Water4,630257
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area890 Å2
ΔGint-13 kcal/mol
Surface area7810 Å2
Unit cell
Length a, b, c (Å)42.854, 52.595, 89.257
Angle α, β, γ (deg.)90, 90, 90
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: 18231.701 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 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P62937, peptidylprolyl isomerase
#2: Chemical ChemComp-A1ILH / (2R,3S,7S,10S,E)-10-(3-aminopropyl)-2,7-dimethylspiro[3,8,11-triaza-1(2,7)-quinolina-5(3,1)-pyridazinacyclopentadecaphanene-13,5'-[1,3]dioxan]-14-ene-4,6,9,12-tetraone


Mass: 607.701 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H41N7O6 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 257 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.76 Å3/Da / Density % sol: 55.41 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 28% PEG-3350, 0.1 M Tris-HCl pH 8.8

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Sep 10, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 1.15→45.31 Å / Num. obs: 71497 / % possible obs: 98.8 % / Redundancy: 7.2 % / CC1/2: 1 / Rmerge(I) obs: 0.038 / Rpim(I) all: 0.022 / Rrim(I) all: 0.044 / Net I/σ(I): 18.9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all
6.3-45.316.60.01952110.0110.022
1.15-1.177.21.34234660.7120.7891.562

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Processing

Software
NameVersionClassification
REFMAC5.8.0425refinement
autoXDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.15→45.004 Å / Cor.coef. Fo:Fc: 0.984 / Cor.coef. Fo:Fc free: 0.983 / SU B: 1.269 / SU ML: 0.024 / Cross valid method: THROUGHOUT / ESU R: 0.026 / ESU R Free: 0.027
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.149 3671 5.139 %
Rwork0.1309 67759 -
all0.132 --
obs-71430 98.653 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 19.689 Å2
Baniso -1Baniso -2Baniso -3
1--0.899 Å2-0 Å20 Å2
2--1.746 Å20 Å2
3----0.847 Å2
Refinement stepCycle: LAST / Resolution: 1.15→45.004 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1267 0 45 257 1569
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0121362
X-RAY DIFFRACTIONr_bond_other_d0.0030.0161246
X-RAY DIFFRACTIONr_angle_refined_deg1.861.8621834
X-RAY DIFFRACTIONr_angle_other_deg0.8131.8192878
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.265169
X-RAY DIFFRACTIONr_dihedral_angle_2_deg7.65357
X-RAY DIFFRACTIONr_dihedral_angle_3_deg9.710216
X-RAY DIFFRACTIONr_dihedral_angle_6_deg13.8631061
X-RAY DIFFRACTIONr_chiral_restr0.1080.2187
X-RAY DIFFRACTIONr_chiral_restr_other1.1070.213
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.021618
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02331
X-RAY DIFFRACTIONr_nbd_refined0.2610.2219
X-RAY DIFFRACTIONr_symmetry_nbd_other0.210.21162
X-RAY DIFFRACTIONr_nbtor_refined0.1850.2697
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0890.2663
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1560.2142
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.1880.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.0270.26
X-RAY DIFFRACTIONr_nbd_other0.1490.225
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2180.223
X-RAY DIFFRACTIONr_mcbond_it4.661.656679
X-RAY DIFFRACTIONr_mcbond_other4.6571.655680
X-RAY DIFFRACTIONr_mcangle_it6.1332.972847
X-RAY DIFFRACTIONr_mcangle_other6.1292.971848
X-RAY DIFFRACTIONr_scbond_it6.1421.881683
X-RAY DIFFRACTIONr_scbond_other6.1391.883684
X-RAY DIFFRACTIONr_scangle_it8.4663.36987
X-RAY DIFFRACTIONr_scangle_other8.4623.361988
X-RAY DIFFRACTIONr_lrange_it15.01422.8641573
X-RAY DIFFRACTIONr_lrange_other12.81117.5331492
X-RAY DIFFRACTIONr_rigid_bond_restr3.90332608
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
1.15-1.180.2862700.2848660.2852740.8960.89797.38340.274
1.18-1.2120.2532570.25447590.25451420.920.91197.54960.243
1.212-1.2470.2632190.23846620.23950080.920.92497.46410.22
1.247-1.2860.232530.21145220.21248860.9370.94197.72820.191
1.286-1.3280.1952500.19343750.19347250.9570.95697.88360.17
1.328-1.3740.1982080.16643070.16745880.9570.96998.40890.141
1.374-1.4260.152190.13741290.13744120.9790.97998.54940.113
1.426-1.4840.1512280.12539920.12742690.9780.98498.85220.101
1.484-1.550.1322150.138550.10241000.9860.99299.26830.083
1.55-1.6260.1351920.0936970.09239100.9860.99499.46290.075
1.626-1.7140.1291900.08535220.08737430.9890.99599.17180.073
1.714-1.8170.1191920.08633450.08835500.9910.99599.63380.077
1.817-1.9430.1411920.09931380.10133390.9870.99499.73050.09
1.943-2.0980.1341660.10529180.10631100.9880.99399.1640.1
2.098-2.2980.1431540.11427290.11528880.9880.99299.82690.111
2.298-2.5680.1281360.10124690.10226070.990.99499.92330.102
2.568-2.9640.1321250.1122100.11123400.9890.99299.78630.116
2.964-3.6260.121870.13418890.13319900.9910.98999.29650.146
3.626-5.1110.134710.13514910.13515780.9910.9998.98610.157
5.111-45.0040.227470.2078840.2089450.9690.97498.51850.239

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