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- PDB-3odi: Crystal structure of cyclophilin A in complex with Voclosporin E-... -

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Basic information

Entry
Database: PDB / ID: 3odi
TitleCrystal structure of cyclophilin A in complex with Voclosporin E-ISA247
Components
  • Cyclophilin APeptidylprolyl isomerase A
  • Voclosporin
KeywordsISOMERASE/IMMUNOSUPPRESSANT / CALCINEURIN INHIBITION / CALCINEURIN / CYCLOSPORIN / PSORIASIS / IMMUNOSUPPRESSANT / VOCLOSPORIN / ISOMERASE-IMMUNOSUPPRESSANT 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
: / Peptidyl-prolyl cis-trans isomerase A / Peptidyl-prolyl cis-trans isomerase A
Similarity search - Component
Biological speciesHomo sapiens (human)
Tolypocladium inflatum (fungus)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsKuglstatter, A. / Stihle, M. / Benz, J. / Hennig, M.
CitationJournal: Acta Crystallogr.,Sect.D / Year: 2011
Title: Structural basis for the cyclophilin A binding affinity and immunosuppressive potency of E-ISA247 (voclosporin).
Authors: Kuglstatter, A. / Mueller, F. / Kusznir, E. / Gsell, B. / Stihle, M. / Thoma, R. / Benz, J. / Aspeslet, L. / Freitag, D. / Hennig, M.
History
DepositionAug 11, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 16, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 6, 2021Group: Database references / Derived calculations / Category: database_2 / struct_conn / struct_ref_seq_dif
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_ref_seq_dif.details
Revision 1.3Sep 6, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.4Dec 6, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cyclophilin A
B: Voclosporin
C: Cyclophilin A
D: Voclosporin
E: Cyclophilin A
F: Voclosporin
G: Cyclophilin A
H: Voclosporin
I: Cyclophilin A
J: Voclosporin
K: Cyclophilin A
L: Voclosporin
M: Cyclophilin A
N: Voclosporin
O: Cyclophilin A
P: Voclosporin
Q: Cyclophilin A
R: Voclosporin
S: Cyclophilin A
T: Voclosporin


Theoretical massNumber of molelcules
Total (without water)192,69120
Polymers192,69120
Non-polymers00
Water27,2031510
1
A: Cyclophilin A
B: Voclosporin


Theoretical massNumber of molelcules
Total (without water)19,2692
Polymers19,2692
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1030 Å2
ΔGint-6 kcal/mol
Surface area7840 Å2
MethodPISA
2
C: Cyclophilin A
D: Voclosporin


Theoretical massNumber of molelcules
Total (without water)19,2692
Polymers19,2692
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area970 Å2
ΔGint-6 kcal/mol
Surface area7650 Å2
MethodPISA
3
E: Cyclophilin A
F: Voclosporin


Theoretical massNumber of molelcules
Total (without water)19,2692
Polymers19,2692
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area970 Å2
ΔGint-6 kcal/mol
Surface area7850 Å2
MethodPISA
4
G: Cyclophilin A
H: Voclosporin


Theoretical massNumber of molelcules
Total (without water)19,2692
Polymers19,2692
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1000 Å2
ΔGint-6 kcal/mol
Surface area7800 Å2
MethodPISA
5
I: Cyclophilin A
J: Voclosporin


Theoretical massNumber of molelcules
Total (without water)19,2692
Polymers19,2692
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area970 Å2
ΔGint-7 kcal/mol
Surface area7860 Å2
MethodPISA
6
K: Cyclophilin A
L: Voclosporin


Theoretical massNumber of molelcules
Total (without water)19,2692
Polymers19,2692
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1010 Å2
ΔGint-6 kcal/mol
Surface area7900 Å2
MethodPISA
7
M: Cyclophilin A
N: Voclosporin


Theoretical massNumber of molelcules
Total (without water)19,2692
Polymers19,2692
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1030 Å2
ΔGint-6 kcal/mol
Surface area7740 Å2
MethodPISA
8
O: Cyclophilin A
P: Voclosporin


Theoretical massNumber of molelcules
Total (without water)19,2692
Polymers19,2692
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area960 Å2
ΔGint-6 kcal/mol
Surface area7870 Å2
MethodPISA
9
Q: Cyclophilin A
R: Voclosporin


Theoretical massNumber of molelcules
Total (without water)19,2692
Polymers19,2692
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1020 Å2
ΔGint-6 kcal/mol
Surface area7730 Å2
MethodPISA
10
S: Cyclophilin A
T: Voclosporin


Theoretical massNumber of molelcules
Total (without water)19,2692
Polymers19,2692
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area990 Å2
ΔGint-6 kcal/mol
Surface area7880 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.179, 161.341, 93.654
Angle α, β, γ (deg.)90.00, 100.06, 90.00
Int Tables number4
Space group name H-MP1211
DetailsThe asymmetric unit of the crystal contains ten pharmacological units.

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Components

#1: Protein
Cyclophilin A / Peptidylprolyl isomerase A / Peptidyl-prolyl cis-trans isomerase


Mass: 18036.504 Da / Num. of mol.: 10
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPIA / Plasmid: pET21a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: A8K220, UniProt: P62937*PLUS, peptidylprolyl isomerase
#2: Protein/peptide
Voclosporin / / E-ISA247 / ISATX-247 / LUVENIQ


Mass: 1232.635 Da / Num. of mol.: 10 / Source method: obtained synthetically / Details: A MODIFIED CYCLOSPORIN A / Source: (synth.) Tolypocladium inflatum (fungus) / References: NOR: NOR00033
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1510 / Source method: isolated from a natural source / Formula: H2O
Compound detailsVOCLOSPORIN IS A CYCLOSPORIN ANALOG, A CYCLIC UNDECAPEPTIDE. HERE, VOCLOSPORIN IS REPRESENTED BY ...VOCLOSPORIN IS A CYCLOSPORIN ANALOG, A CYCLIC UNDECAPEPTIDE. HERE, VOCLOSPORIN IS REPRESENTED BY THE SEQUENCE (SEQRES). RESIDUE 1 IS LINKED TO RESIDUE 11 VIA A PEPTIDE BOND. IT DIFFERS FROM CYCLOSPORIN A IN POSITION 5. AUTHOR STATES THAT THE E-ISA247 (VOCLOSPORIN) ANTIBIOTIC IN THIS STRUCTURE IS NOT NATURAL PRODUCT, RATHER IT IS NEWLY DESIGNED COMPOUND. THE CLOSEST MATCH IN NORINE DATABASE IS CYCLOSPORIN A, WITH A DIFFERENCE AT RESIDUE 5 ALTERED FROM N-METHYL-4-BUTENYL-4-METHYL THREONINE (WITH PROTEIN DATA BANK LIGAND CODE BMT) TO 2,4,5-TRIDEOXY-2-(METHYLAMINO)-4-[(2E)-PENTA-2,4-DIEN-1-YL]-L-XYLONIC ACID(LIGAND CODE XXA)

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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: 2.67 Å3/Da / Density % sol: 53.94 %
Crystal growTemperature: 295 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 20% PEG3350, 0.1M MES, 0.2M ammonium sulphate, pH 6.5, VAPOR DIFFUSION, HANGING DROP, temperature 295K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: OTHER / Wavelength: 1.5418 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.2→25 Å / Num. obs: 93907 / % possible obs: 91.8 % / Redundancy: 3.3 % / Rsym value: 0.082 / Net I/σ(I): 13.3
Reflection shellResolution: 2.2→2.28 Å / Redundancy: 3.1 % / Mean I/σ(I) obs: 2.6 / Rsym value: 0.399 / % possible all: 88

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Processing

Software
NameVersionClassification
MAR345dtbdata collection
MOLREPphasing
REFMAC5.1.24refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 2RMA

2rma


Resolution: 2.2→25 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.924 / SU B: 5.43 / SU ML: 0.138 / Cross valid method: THROUGHOUT / ESU R Free: 0.207 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.21966 4673 5 %RANDOM
Rwork0.16354 ---
obs0.16633 89178 91.82 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 36.425 Å2
Baniso -1Baniso -2Baniso -3
1--0.26 Å20 Å2-0.19 Å2
2---0.77 Å20 Å2
3---0.96 Å2
Refinement stepCycle: LAST / Resolution: 2.2→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13462 0 0 1510 14972
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.02113742
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.0921.97118415
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.55551744
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_dihedral_angle_3_deg
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0780.21964
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0210356
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.1870.26843
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1060.21359
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1740.248
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1110.226
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.3541.58655
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.678213757
X-RAY DIFFRACTIONr_scbond_it1.08335087
X-RAY DIFFRACTIONr_scangle_it1.8534.54658
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.2→2.257 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.266 296
Rwork0.198 6439

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