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- PDB-7th7: Structure of Cyclophilin D Peptidyl-Prolyl Isomerase Domain bound... -

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Basic information

Entry
Database: PDB / ID: 7th7
TitleStructure of Cyclophilin D Peptidyl-Prolyl Isomerase Domain bound to Macrocyclic Inhibitor B23
ComponentsPeptidyl-prolyl cis-trans isomerase F, mitochondrial
KeywordsISOMERASE / oxidative stress / necrosis / mitochondrial permeability
Function / homology
Function and homology information


regulation of proton-transporting ATPase activity, rotational mechanism / negative regulation of oxidative phosphorylation uncoupler activity / 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 / negative regulation of ATP-dependent activity / cellular response to arsenic-containing substance / mitochondrial depolarization / negative regulation of oxidative phosphorylation ...regulation of proton-transporting ATPase activity, rotational mechanism / negative regulation of oxidative phosphorylation uncoupler activity / 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 / negative regulation of ATP-dependent activity / cellular response to arsenic-containing substance / mitochondrial depolarization / negative regulation of oxidative phosphorylation / regulation of mitochondrial membrane permeability / cyclosporin A binding / negative regulation of release of cytochrome c from mitochondria / necroptotic process / apoptotic mitochondrial changes / protein peptidyl-prolyl isomerization / negative regulation of intrinsic apoptotic signaling pathway / cellular response to calcium ion / response to ischemia / peptidylprolyl isomerase / peptidyl-prolyl cis-trans isomerase activity / peptide binding / cellular response to hydrogen peroxide / protein folding / mitochondrial inner membrane / mitochondrial matrix / negative regulation of apoptotic process / mitochondrion / membrane / cytoplasm
Similarity search - Function
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
Chem-I5E / Peptidyl-prolyl cis-trans isomerase F, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.3 Å
AuthorsRangwala, A.M. / Thakur, M.K. / Seeliger, M.A. / Peterson, A.A. / Liu, D.R.
Funding support United States, 6items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)CA260772 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM118062 United States
National Institutes of Health/National Institute of Biomedical Imaging and Bioengineering (NIH/NIBIB)EB022376 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM119437 United States
National Institutes of Health/Office of the DirectorOD028478 United States
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: Nat.Chem.Biol. / Year: 2022
Title: Discovery and molecular basis of subtype-selective cyclophilin inhibitors.
Authors: Peterson, A.A. / Rangwala, A.M. / Thakur, M.K. / Ward, P.S. / Hung, C. / Outhwaite, I.R. / Chan, A.I. / Usanov, D.L. / Mootha, V.K. / Seeliger, M.A. / Liu, D.R.
History
DepositionJan 10, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 24, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 12, 2022Group: Database references / Category: citation / citation_author
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 1.2Nov 2, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)18,5252
Polymers17,5951
Non-polymers9301
Water3,963220
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)38.542, 67.177, 69.071
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP22121
Space group name HallP22ab(z,x,y)
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y+1/2,-z+1/2
#4: -x,-y+1/2,z+1/2

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Components

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


Mass: 17595.074 Da / Num. of mol.: 1 / Mutation: K175I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PPIF, CYP3 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / References: UniProt: P30405, peptidylprolyl isomerase
#2: Chemical ChemComp-I5E / 3-(4'-{[(4S,7S,11R,19S)-19-{[2-(2-aminoethoxy)ethyl]carbamoyl}-7-benzyl-3,6,12,15,21-pentaoxo-1,3,4,5,6,7,8,9,10,12,13,14,15,16,17,18,19,20,21,22-icosahydro-2H-7,11-methano-2,5,11,16,20-benzopentaazacyclotetracosin-4-yl]methyl}[1,1'-biphenyl]-4-yl)propanoic acid


Mass: 930.098 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C52H63N7O9 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 220 / 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: 2.47 Å3/Da / Density meas: 49.3 Mg/m3 / Density % sol: 51.59 % / Description: Bladed, tabular, roughly 0.3-0.5 mm in length
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.2
Details: 21% PEG 3350 0.5 M KH2PO4 Protein and inhibitor were mixed in ratio 1:3 1 uL of protein:inhibitor complex was mixed with 1 uL mother liquor

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-2 / Wavelength: 0.97931 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Aug 21, 2020
RadiationMonochromator: Double Crystal Monochromator; Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97931 Å / Relative weight: 1
ReflectionResolution: 1.3→25.72 Å / Num. obs: 46222 / % possible obs: 93.8 % / Redundancy: 11.4 % / Biso Wilson estimate: 9.38 Å2 / CC1/2: 0.998 / CC star: 1 / Rmerge(I) obs: 0.078 / Rpim(I) all: 0.01896 / Rrim(I) all: 0.02682 / Net I/σ(I): 19
Reflection shellResolution: 1.3→1.34 Å / Num. unique obs: 393 / CC1/2: 0.911 / % possible all: 60

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
Cootmodel building
XDSdata reduction
autoPROCdata scaling
autoPROCdata processing
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2BIT

2bit


Resolution: 1.3→25.72 Å / SU ML: 0.0773 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 13.3911
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1473 1831 4.35 %
Rwork0.135 40283 -
obs0.1355 42114 93.8 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 12.77 Å2
Refinement stepCycle: LAST / Resolution: 1.3→25.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1236 0 68 220 1524
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00931374
X-RAY DIFFRACTIONf_angle_d1.20021857
X-RAY DIFFRACTIONf_chiral_restr0.0849195
X-RAY DIFFRACTIONf_plane_restr0.0089240
X-RAY DIFFRACTIONf_dihedral_angle_d32.8235204
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.3-1.340.1866870.18731962X-RAY DIFFRACTION60.07
1.34-1.370.20741120.15622404X-RAY DIFFRACTION73.98
1.37-1.420.15991320.13472868X-RAY DIFFRACTION88.13
1.42-1.470.13871420.12533158X-RAY DIFFRACTION97
1.47-1.530.12521460.1183243X-RAY DIFFRACTION99.21
1.53-1.60.11521510.11663264X-RAY DIFFRACTION99.97
1.6-1.680.12741450.12163293X-RAY DIFFRACTION99.97
1.68-1.790.13891550.12643264X-RAY DIFFRACTION100
1.79-1.930.17021490.12323322X-RAY DIFFRACTION100
1.93-2.120.13861520.12463282X-RAY DIFFRACTION100
2.12-2.430.13611470.12533339X-RAY DIFFRACTION100
2.43-3.060.14451510.14143366X-RAY DIFFRACTION100
3.06-25.720.15921620.15073518X-RAY DIFFRACTION99.97
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)
10.03554523688070.0715228769916-0.03777902721810.4041140610530.01637017034550.26657866333-0.02262040289740.0345215252405-0.1054594720870.04943982753880.01642498172860.04714736693930.0162601054585-0.00953951866599-5.32973364481E-50.0856472689910.003413733170380.001077741663950.0832820384526-0.003413851524830.102154824951-3.413670971813.3085254628117.1057064002
20.2005248776080.0444170393618-0.05057449528450.254633595766-0.01949306504190.1836499519540.0200127062696-0.0550108082848-0.1224020969150.0826239777258-0.0127791190066-0.1582870786650.1018516737160.1330112161930.001814852708160.07061936745190.00579694374257-0.003716656861430.0931022820388-0.001714537297470.0894471811358.548502363579.5200286598124.6504559221
30.09798547107440.1246352367770.06612043815960.2447255039820.1375744722250.08945981495650.022489779701-0.002511899396330.01542694147110.0115433054624-0.01459473620650.03947571883980.0135515380068-0.006595381081030.004186729561540.0732829479678-0.002260102829610.001019879703730.0811870036815-0.004013844889990.0658849684566-4.3368269940914.642154776818.3679428853
40.216019992970.216560899313-0.2566334256570.30453935141-0.3489992587040.43491220364-0.0105668645385-0.1436242851270.1000760887620.2063691823530.05079801463450.220390153928-0.0628115738729-0.121192078040.001165044017550.0812446818084-0.001278209559410.006492274469770.0909158065927-0.009012991123370.0905512077614-7.4001004452820.558175919123.9320172051
50.05299327923260.01507109806280.03749482183880.008542987658470.003762729946280.0913420973872-0.00280250703141-0.06125161882770.06596567760160.08119945829520.0099528275632-0.0427567962817-0.1030292915850.04140538465960.0003991960169940.09477447905510.00382664170662-0.002831375562610.0894716703608-0.007654878686750.07200556203175.2523163145820.597983567329.426210821
60.559450669646-0.1269371149950.1131909500180.8835764587440.5674211171430.872165265644-0.002108849238020.06721913437720.034856395061-0.08205219166880.038528648069-0.080271181576-0.0855664879430.1165980513770.1486115237850.0665905999655-0.007926990959320.003677340014980.07571443122760.001734349522730.06705278776887.3030766491116.531110356513.7082836735
70.04318437118410.03369000688010.01421804190880.150664704856-0.03024765816080.07814498077740.1287297287480.08184061628330.0389599230497-0.101547909569-0.0919368740977-0.1088403684590.04974674099450.02357494039520.001220027032290.09510782205420.000992128545368-0.004872382350180.08637502491931.38649065229E-50.0983128280686-6.869504975557.763246190197.04125406056
80.654975255920.314721446877-0.5185669135640.4306119786770.2322117305541.239616569150.0728340521707-0.03507325400770.161429066764-0.09052210250790.01884506456430.198118937051-0.240754979632-0.0829954855291-0.001995598851440.08589138256780.0184186723889-0.008098064124540.09740516279370.005505810835250.112207551017-13.004492843318.44668526899.297053914
90.1196076069050.109589360413-0.0720799635510.122735189213-0.02085433048860.2294798679730.0635082317447-0.0231224586093-0.1891538638550.0627219948669-0.05370288985330.05491557966620.1945037170040.0339943620474-0.005051022135620.1075195708450.00189414381198-0.007416344836880.09102926891580.0008215090809510.1007716849-4.066535316363.7607827204322.0259856512
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 45 through 66 )
2X-RAY DIFFRACTION2chain 'A' and (resid 67 through 83 )
3X-RAY DIFFRACTION3chain 'A' and (resid 84 through 106 )
4X-RAY DIFFRACTION4chain 'A' and (resid 107 through 116 )
5X-RAY DIFFRACTION5chain 'A' and (resid 117 through 126 )
6X-RAY DIFFRACTION6chain 'A' and (resid 127 through 177 )
7X-RAY DIFFRACTION7chain 'A' and (resid 178 through 187 )
8X-RAY DIFFRACTION8chain 'A' and (resid 188 through 197 )
9X-RAY DIFFRACTION9chain 'A' and (resid 198 through 207 )

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