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- PDB-6x4o: Human cyclophilin A bound to a series of acylcic and macrocyclic ... -

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Basic information

Entry
Database: PDB / ID: 6x4o
TitleHuman cyclophilin A bound to a series of acylcic and macrocyclic inhibitors: (2R,5S,11S,14S,18E)-2,11-dimethyl-14-(propan-2-yl)-3-oxa-9,12,15,21,29-pentaazatetracyclo[18.5.3.1~5,9~.0~23,27~]nonacosa-1(26),18,20,22,24,27-hexaene-4,10,13,16-tetrone (compound 21)
ComponentsPeptidyl-prolyl cis-trans isomerase A
KeywordsISOMERASE/ISOMERASE INHIBITOR / Cyclophilin A / Sanglifehrin A / prolyl isomerase / macrocylcic inhibitor / peptidomimetic / 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
Chem-UO7 / Peptidyl-prolyl cis-trans isomerase A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 Å
AuthorsAppleby, T.C. / Paulsen, J.L. / Schmitz, U. / Shivakumar, D.
CitationJournal: J.Chem.Inf.Model. / Year: 2020
Title: Evaluation of Free Energy Calculations for the Prioritization of Macrocycle Synthesis.
Authors: Paulsen, J.L. / Yu, H.S. / Sindhikara, D. / Wang, L. / Appleby, T. / Villasenor, A.G. / Schmitz, U. / Shivakumar, D.
History
DepositionMay 22, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 24, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 1, 2020Group: Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Aug 26, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.3Oct 18, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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)18,7532
Polymers18,2321
Non-polymers5221
Water3,693205
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area7080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)43.216, 51.893, 89.260
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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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 (E. coli) / References: UniProt: P62937, peptidylprolyl isomerase
#2: Chemical ChemComp-UO7 / (2R,5S,11S,14S,18E)-2,11-dimethyl-14-(propan-2-yl)-3-oxa-9,12,15,21,29-pentaazatetracyclo[18.5.3.1~5,9~.0~23,27~]nonacosa-1(26),18,20,22,24,27-hexaene-4,10,13,16-tetrone


Mass: 521.608 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H35N5O5 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 205 / Source method: isolated from a natural source / Formula: H2O
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: 2.74 Å3/Da / Density % sol: 55.19 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8.5
Details: 20 mM Tris-HCl, pH 8.5, 2 mM DTT, 2 mM EDTA, 20-35% PEG3350, 5% ethanol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.976 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 29, 2011
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 1.5→33.84 Å / Num. obs: 32538 / % possible obs: 97.7 % / Redundancy: 4.1 % / Biso Wilson estimate: 18.74 Å2 / Rsym value: 0.05 / Net I/σ(I): 23.75
Reflection shellResolution: 1.5→1.54 Å / Num. unique obs: 1878 / Rsym value: 0.376 / % possible all: 80.3

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
PHENIX1.17.1_3660refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 2CPL

2cpl


Resolution: 1.5→33.84 Å / SU ML: 0.1423 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 21.1692
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1984 2000 6.16 %
Rwork0.178 30480 -
obs0.1793 32480 97.46 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 22.39 Å2
Refinement stepCycle: LAST / Resolution: 1.5→33.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1222 0 38 205 1465
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00961291
X-RAY DIFFRACTIONf_angle_d1.07531740
X-RAY DIFFRACTIONf_chiral_restr0.0929181
X-RAY DIFFRACTIONf_plane_restr0.0073229
X-RAY DIFFRACTIONf_dihedral_angle_d11.6913176
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.49-1.530.25261090.24361672X-RAY DIFFRACTION76.37
1.53-1.570.25181370.22762067X-RAY DIFFRACTION94.07
1.57-1.620.28051420.21312171X-RAY DIFFRACTION99.14
1.62-1.670.22191450.20022215X-RAY DIFFRACTION99.75
1.67-1.730.23321450.20262212X-RAY DIFFRACTION99.92
1.73-1.80.22711450.19492211X-RAY DIFFRACTION99.75
1.8-1.880.2391440.18732194X-RAY DIFFRACTION99.83
1.88-1.980.22131450.18832197X-RAY DIFFRACTION99.66
1.98-2.10.20281450.1832217X-RAY DIFFRACTION99.92
2.1-2.270.22281460.1782234X-RAY DIFFRACTION99.79
2.27-2.50.21751480.17962243X-RAY DIFFRACTION99.79
2.5-2.860.19491470.18282238X-RAY DIFFRACTION99.71
2.86-3.60.20161490.17792281X-RAY DIFFRACTION99.22
3.6-33.840.15041530.15272328X-RAY DIFFRACTION97.29

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