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- PDB-6r8l: Human Cyclophilin D in complex with 1-((1S,9S,10S)-10-Hydroxy-12-... -

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Basic information

Entry
Database: PDB / ID: 6r8l
TitleHuman Cyclophilin D in complex with 1-((1S,9S,10S)-10-Hydroxy-12-oxa-8-aza-tricyclo[7.3.1.02,7]trideca-2,4,6-trien-4-ylmethyl)-3- {2-[(R)-2-(2-methylsulfanyl-phenyl)-pyrrolidin-1-yl]-2-oxo-ethyl}-urea
ComponentsPeptidyl-prolyl cis-trans isomerase F, mitochondrial
KeywordsISOMERASE / CYCLOPHILIN / BETA BARREL / PROLYL CIS/TRANS ISOMERASE / MITOC
Function / homology
Function and homology information


: / : / mitochondrial outer membrane permeabilization involved in programmed cell death / regulation of mitochondrial membrane permeability involved in programmed necrotic cell death / skeletal muscle fiber differentiation / mitochondrial permeability transition pore complex / cellular response to arsenic-containing substance / negative regulation of ATP-dependent activity / mitochondrial depolarization / negative regulation of oxidative phosphorylation ...: / : / mitochondrial outer membrane permeabilization involved in programmed cell death / regulation of mitochondrial membrane permeability involved in programmed necrotic cell death / skeletal muscle fiber differentiation / mitochondrial permeability transition pore complex / cellular response to arsenic-containing substance / negative regulation of ATP-dependent activity / mitochondrial depolarization / negative regulation of oxidative phosphorylation / regulation of mitochondrial membrane permeability / cyclosporin A binding / negative regulation of release of cytochrome c from mitochondria / negative regulation of intrinsic apoptotic signaling pathway / necroptotic process / apoptotic mitochondrial changes / cellular response to calcium ion / response to ischemia / peptidylprolyl isomerase / peptidyl-prolyl cis-trans isomerase activity / cellular response to hydrogen peroxide / protein folding / mitochondrial matrix / negative regulation of apoptotic process / mitochondrion / membrane / cytoplasm
Similarity search - Function
Cyclophilin-like / Cyclophilin / 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-JUZ / Peptidyl-prolyl cis-trans isomerase F, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.64 Å
AuthorsGraedler, U.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2019
Title: Discovery of novel Cyclophilin D inhibitors starting from three dimensional fragments with millimolar potencies.
Authors: Gradler, U. / Schwarz, D. / Blaesse, M. / Leuthner, B. / Johnson, T.L. / Bernard, F. / Jiang, X. / Marx, A. / Gilardone, M. / Lemoine, H. / Roche, D. / Jorand-Lebrun, C.
History
DepositionApr 2, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 27, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 24, 2024Group: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_atoms
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 F, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,1492
Polymers17,6521
Non-polymers4971
Water3,009167
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area7140 Å2
Unit cell
Length a, b, c (Å)57.151, 57.151, 115.386
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212

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Components

#1: Protein Peptidyl-prolyl cis-trans isomerase F, mitochondrial / PPIase F / Cyclophilin D / CypD / Cyclophilin F / Mitochondrial cyclophilin / CyP-M / Rotamase F


Mass: 17652.125 Da / Num. of mol.: 1 / Fragment: 44-207 (K175I) / Mutation: K175I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPIF, CYP3 / Production host: Escherichia coli (E. coli) / References: UniProt: P30405, peptidylprolyl isomerase
#2: Chemical ChemComp-JUZ / 1-[2-[(2~{R})-2-(2-methylsulfanylphenyl)pyrrolidin-1-yl]-2-oxidanylidene-ethyl]-3-[[(1~{S},9~{S},10~{S})-10-oxidanyl-12-oxa-8-azatricyclo[7.3.1.0^{2,7}]trideca-2(7),3,5-trien-4-yl]methyl]urea


Mass: 496.622 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H32N4O4S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 167 / 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: 2.67 Å3/Da / Density % sol: 53.91 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 7.5 / Details: PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.82655 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Jun 18, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.82655 Å / Relative weight: 1
ReflectionResolution: 1.64→51.21 Å / Num. obs: 23444 / % possible obs: 96.8 % / Redundancy: 2.73 % / Biso Wilson estimate: 23.16 Å2 / Rmerge(I) obs: 0.047 / Net I/σ(I): 14.79
Reflection shellResolution: 1.64→1.89 Å / Redundancy: 2.7 % / Rmerge(I) obs: 0.478 / Mean I/σ(I) obs: 2.13 / Num. unique obs: 7936 / % possible all: 96.9

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5refinement
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4J5B

4j5b


Resolution: 1.64→51.21 Å / Cor.coef. Fo:Fc: 0.9474 / Cor.coef. Fo:Fc free: 0.9313 / SU R Cruickshank DPI: 0.083 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.092 / SU Rfree Blow DPI: 0.09 / SU Rfree Cruickshank DPI: 0.085
RfactorNum. reflection% reflectionSelection details
Rfree0.2028 2373 10.13 %RANDOM
Rwork0.1728 ---
obs0.1759 23430 96.89 %-
Displacement parametersBiso mean: 28.99 Å2
Baniso -1Baniso -2Baniso -3
1-5.7998 Å20 Å20 Å2
2--5.7998 Å20 Å2
3----11.5995 Å2
Refine analyzeLuzzati coordinate error obs: 0.234 Å
Refinement stepCycle: LAST / Resolution: 1.64→51.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1248 0 35 167 1450
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.011315HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.031777HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d444SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes28HARMONIC2
X-RAY DIFFRACTIONt_gen_planes195HARMONIC5
X-RAY DIFFRACTIONt_it1315HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.53
X-RAY DIFFRACTIONt_other_torsion13.9
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion167SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact1645SEMIHARMONIC4
LS refinement shellResolution: 1.64→1.71 Å / Total num. of bins used: 12
RfactorNum. reflection% reflection
Rfree0.2759 271 9.84 %
Rwork0.2527 2482 -
all0.2551 2753 -
obs--96.89 %
Refinement TLS params.Method: refined / Origin x: -10.397 Å / Origin y: -8.544 Å / Origin z: -23.029 Å
111213212223313233
T0.075 Å2-0.0039 Å20.0556 Å2-0.0064 Å2-0.0064 Å2--0.1104 Å2
L1.9931 °20.2281 °2-0.805 °2-0.9245 °2-0.1651 °2--0.9289 °2
S-0.1041 Å °0.182 Å °-0.1998 Å °0.0164 Å °0.0217 Å °0.0214 Å °0.0881 Å °-0.0589 Å °0.0823 Å °
Refinement TLS groupSelection details: { A|44 - A|207 }

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