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- PDB-7pcj: X-ray structure of CypA-C52AK125C/CsA/aromatic foldamer complex -

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Basic information

Entry
Database: PDB / ID: 7pcj
TitleX-ray structure of CypA-C52AK125C/CsA/aromatic foldamer complex
Components
  • Cyclosporin ACiclosporin
  • Peptidyl-prolyl cis-trans isomerase A
KeywordsCYTOSOLIC PROTEIN / aromatic foldamer disulfide tether cysteine mutant
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 / Binding and entry of HIV virion / positive regulation of viral genome replication / 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 / 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 / response to hypoxia / 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-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
Cyclosporin A / Chem-7I7 / Chem-7IB / Chem-QUJ / Chem-QUK / 8-azanyl-4-oxidanyl-quinoline-2-carboxylic acid / polypeptide(D) / polypeptide(D) (> 10) / Peptidyl-prolyl cis-trans isomerase A
Similarity search - Component
Biological speciesHomo sapiens (human)
Tolypocladium inflatum (fungus)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.91 Å
AuthorsVallade, M. / Langlois d'Estaintot, B. / Fischer, L. / Buratto, J. / Savko, M. / Huc, I.
Funding support France, 1items
OrganizationGrant numberCountry
Other government France
CitationJournal: To Be Published
Title: X-ray structure of a cystein mutant of Cyclophilin A tethered to an aromatic oligoamide foldamer complexed with Cyclosporin A
Authors: Fischer, L. / Savko, M. / Langlois d'Estaintot, B. / Buratto, J. / Vallade, M. / Huc, I.
History
DepositionAug 3, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 13, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 31, 2024Group: Data collection / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model / struct_conn
Item: _struct_conn.pdbx_leaving_atom_flag

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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: Cyclosporin A
D: Peptidyl-prolyl cis-trans isomerase A
E: Cyclosporin A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)41,60216
Polymers38,4624
Non-polymers3,13912
Water2,270126
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: homology, Homology of the CypA/CsA complex with 1CWA structure, mass spectrometry, CypA-foldamer covalently linked via a disulfide bridge (identified by MS and supported by solution NMR studies)
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2610 Å2
ΔGint-14 kcal/mol
Surface area16430 Å2
MethodPISA
Unit cell
Length a, b, c (Å)42.474, 70.891, 64.090
Angle α, β, γ (deg.)90.000, 102.700, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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Protein / Polypeptide(D) , 2 types, 4 molecules ADBE

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


Mass: 18010.467 Da / Num. of mol.: 2 / Mutation: K125C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPIA, CYPA / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): pLysY / References: UniProt: P62937, peptidylprolyl isomerase
#2: Polypeptide(D) Cyclosporin A / Ciclosporin / Ciclosporin


Type: Cyclic peptide / Class: ImmunosuppressantImmunosuppressive drug / Mass: 1220.625 Da / Num. of mol.: 2 / Source method: isolated from a natural source
Details: cyclic undecapeptide, CYCLOSPORIN IS A CYCLIC UNDECAPEPTIDE. CYCLIZATION IS ACHIEVED BY LINKING THE N- AND THE C- TERMINI.
Source: (natural) Tolypocladium inflatum (fungus) / References: Cyclosporin A

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Non-polymers , 6 types, 138 molecules

#3: Chemical ChemComp-7I7 / N-[2-[2-[2-(2-formamidoethoxy)ethoxy]ethoxy]ethyl]-3-sulfanyl-propanamide


Mass: 308.394 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C12H24N2O5S
#4: Chemical
ChemComp-QUK / 8-azanyl-4-(3-azanylpropoxy)quinoline-2-carboxylic acid


Mass: 261.276 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C13H15N3O3
#5: Chemical ChemComp-QVS / 8-azanyl-4-oxidanyl-quinoline-2-carboxylic acid


Mass: 204.182 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H8N2O3
#6: Chemical ChemComp-QUJ / 8-azanyl-4-(2-methylpropoxy)quinoline-2-carboxylic acid


Mass: 260.288 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H16N2O3
#7: Chemical ChemComp-7IB / 8-azanyl-5-(4-oxidanyl-4-oxidanylidene-butyl)quinoline-2-carboxylic acid


Mass: 274.272 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H14N2O4
#8: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 126 / Source method: isolated from a natural source / Formula: H2O

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Details

Compound detailsCYCLOSPORIN IS A CYCLIC UNDECAPEPTIDE. HERE, CYCLOSPORIN A IS REPRESENTED BY THE SEQUENCE (SEQRES)
Has ligand of interestY

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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: 2.69 Å3/Da / Density % sol: 54.29 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.4 / Details: Tris 0.1M, PEG 3350 15%, NaN3 3mM

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 2 / Wavelength: 0.9801 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Feb 1, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9801 Å / Relative weight: 1
ReflectionResolution: 1.91→62.52 Å / Num. obs: 28858 / % possible obs: 100 % / Redundancy: 19.7 % / CC1/2: 0.997 / Rmerge(I) obs: 0.191 / Rpim(I) all: 0.044 / Rrim(I) all: 0.196 / Net I/σ(I): 10.9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.2-2.3216.51.2064476927090.8180.31.2443.1100
6.97-62.52200.095125196270.9970.0210.09822.399.9

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation4 Å62.52 Å
Translation4 Å62.52 Å

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimless0.7.4data scaling
PHASER2.8.3phasing
REFMAC5.8.0258refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2ESL

2esl


Resolution: 1.91→62.52 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.948 / SU B: 9.84 / SU ML: 0.13 / SU R Cruickshank DPI: 0.176 / Cross valid method: FREE R-VALUE / σ(F): 0 / ESU R: 0.176 / ESU R Free: 0.155 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2194 1272 4.9 %RANDOM
Rwork0.1771 ---
obs0.1793 24452 89.09 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 113.38 Å2 / Biso mean: 37.155 Å2 / Biso min: 21.63 Å2
Baniso -1Baniso -2Baniso -3
1--1.64 Å2-0 Å20.94 Å2
2---1.19 Å2-0 Å2
3---2.18 Å2
Refinement stepCycle: final / Resolution: 1.91→62.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2667 0 216 126 3009
Biso mean--59.96 46.59 -
Num. residues----350
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0132959
X-RAY DIFFRACTIONr_bond_other_d0.0030.0182707
X-RAY DIFFRACTIONr_angle_refined_deg1.5681.7533989
X-RAY DIFFRACTIONr_angle_other_deg1.2551.6736249
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.1665334
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.87922.868129
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.37515428
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.041511
X-RAY DIFFRACTIONr_chiral_restr0.0670.2350
X-RAY DIFFRACTIONr_gen_planes_refined0.0130.023364
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02639
LS refinement shellResolution: 1.91→1.959 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.288 21 -
Rwork0.305 277 -
all-298 -
obs--13.94 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.70120.04390.67593.0981.62862.9446-0.0553-0.0325-0.003-0.03620.1246-0.0464-0.066-0.0541-0.06930.1323-0.0131-0.02430.08060.01530.0088-12.918775.639167.1367
23.11651.00252.94198.27290.572.9691-0.1270.2473-0.1082-0.43140.1469-0.1222-0.12930.1485-0.01990.1765-0.0213-0.01530.1134-0.02870.0557-18.782969.852953.6456
31.42840.18630.08521.7582-0.27042.50790.00380.2223-0.0055-0.170.01240.0179-0.0340.0226-0.01620.1714-0.0125-0.03370.17320.03290.01422.753160.170131.7936
47.40110.68772.21234.4913-3.95245.9102-0.05440.16540.28070.53950.16050.1155-0.39920.1521-0.10610.20840.0010.00450.1437-0.02240.022627.588266.476645.1944
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A4 - 167
2X-RAY DIFFRACTION2B1 - 11
3X-RAY DIFFRACTION3D4 - 167
4X-RAY DIFFRACTION4E1 - 11

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