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

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Basic information

Entry
Database: PDB / ID: 7thf
TitleStructure of Cyclophilin D Peptidyl-Prolyl Isomerase Domain bound to Macrocyclic Inhibitor B53
ComponentsPeptidyl-prolyl cis-trans isomerase F, mitochondrial
KeywordsISOMERASE/ISOMERASE INHIBITOR / oxidative stress / necrosis / mitochondrial permeability / ISOMERASE / ISOMERASE-ISOMERASE INHIBITOR complex
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-I4R / Peptidyl-prolyl cis-trans isomerase F, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.1 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)18,6382
Polymers17,6521
Non-polymers9861
Water3,819212
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)38.492, 66.885, 68.968
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: 17652.125 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-I4R / 3-(4'-{[(4S,7S,11R,13E,19S)-19-{[2-(2-aminoethoxy)ethyl]carbamoyl}-7-benzyl-3,6,12,15,21-pentaoxo-1,3,4,5,6,7,8,9,10,12,15,16,17,18,19,20,21,22-octadecahydro-2H-7,11-methano-2,5,11,16,20-benzopentaazacyclotetracosin-4-yl]methyl}[1,1'-biphenyl]-4-yl)pentanedioic acid


Mass: 986.118 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C54H63N7O11 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 212 / 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: 2.38 Å3/Da / Density % sol: 48.3 % / Description: Bladed, tabular, roughly 0.3-0.5 mm in length
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 22.5% PEG 3350 0.5 M KH2PO4 1 mM NaCl Protein and inhibitor were mixed in ratio 1:2 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-1 / Wavelength: 0.92011 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Feb 8, 2021
RadiationMonochromator: Double Crystal Monochromator, Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92011 Å / Relative weight: 1
ReflectionResolution: 1.1→25.68 Å / Num. obs: 71217 / % possible obs: 98.6 % / Redundancy: 13.1 % / Biso Wilson estimate: 12.37 Å2 / CC1/2: 0.994 / CC star: 0.999 / Rmerge(I) obs: 0.18 / Rpim(I) all: 0.0374 / Rrim(I) all: 0.0529 / Net I/σ(I): 9.6
Reflection shellResolution: 1.1→1.13 Å / Redundancy: 11.3 % / Rmerge(I) obs: 0.596 / Mean I/σ(I) obs: 3 / Num. unique obs: 4690 / CC1/2: 0.888 / CC star: 0.98 / Rpim(I) all: 0.1625 / Rrim(I) all: 0.2299 / % possible all: 89.1

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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: 1.1→25.68 Å / SU ML: 0.0672 / Cross valid method: FREE R-VALUE / σ(F): 1.37 / Phase error: 12.9126
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1477 1998 2.81 %
Rwork0.1369 69162 -
obs0.1372 71160 98.51 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 12.37 Å2
Refinement stepCycle: LAST / Resolution: 1.1→25.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1236 0 72 212 1520
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00751384
X-RAY DIFFRACTIONf_angle_d1.06331875
X-RAY DIFFRACTIONf_chiral_restr0.0805196
X-RAY DIFFRACTIONf_plane_restr0.0082244
X-RAY DIFFRACTIONf_dihedral_angle_d20.0812274
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.1-1.130.20031310.18024368X-RAY DIFFRACTION88.34
1.13-1.160.14681340.14914807X-RAY DIFFRACTION96.96
1.16-1.20.15711410.144793X-RAY DIFFRACTION97.57
1.2-1.230.15351410.13694894X-RAY DIFFRACTION98.28
1.23-1.280.12761430.13394927X-RAY DIFFRACTION99.1
1.28-1.330.14211390.14094938X-RAY DIFFRACTION99.39
1.33-1.390.14811380.13474949X-RAY DIFFRACTION99.65
1.39-1.460.14611450.12874989X-RAY DIFFRACTION99.81
1.46-1.560.13111450.12384973X-RAY DIFFRACTION99.84
1.56-1.680.13171470.12445025X-RAY DIFFRACTION100
1.68-1.840.13841380.1225037X-RAY DIFFRACTION100
1.84-2.110.12191500.12315040X-RAY DIFFRACTION100
2.11-2.660.13071520.13025106X-RAY DIFFRACTION100
2.66-25.680.17931540.15435316X-RAY DIFFRACTION99.98
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)
10.2962276901050.0393555527356-0.04262856301820.6400658751070.08168007278880.6530254198110.007389722492990.018064656927-0.1195412415470.0341089849078-0.005283975276240.04598237639510.0444312200933-0.01801798887220.003610795225860.08803869544670.001897120083790.003287390048770.0833063496782-0.003270102690550.102656849331-3.70644066723.1996891396616.9635271486
20.3064929540470.08297540994520.05778180893040.7722349551450.03149251187850.6026722763930.016171273031-0.0191292630459-0.004803818198050.0361618357301-0.0103672484892-0.03001517117230.0221761863490.0208737420380.0005258732271510.06458555789490.0001832195774280.003608003102520.077315276914-0.005850926140380.06709608202120.9677887267612.421686516520.8830972519
30.214267285076-0.1415388977380.01270435312520.127351655471-0.05631724160420.26570272969-0.0387289336869-0.05955734932770.07093814323250.09188982844830.01295785441340.0242711767693-0.0846043983871-0.0179287817608-0.002603604114140.1027699886950.00105179069722-0.00102399142290.0987202082443-0.007918941049180.0903211789294-0.58294812300420.137887716427.0342739498
40.482754186265-0.00467498545360.1902920737720.4259914512170.1611617917080.2216280568960.001459028307130.06561705205220.0496026165049-0.07224989021510.0240214710896-0.0860546595338-0.101631795090.1175181740510.0005102483044810.0889882008539-0.009153476714530.002985733288530.09220708267510.002233390102760.0879021576447.112598490517.962090587914.0015581091
50.3760461873930.0004921437900570.04309255083820.336022233476-0.001868842498460.278032699029-0.02136670700070.0779885250692-0.0513091106355-0.1576183833750.0675479876259-0.076597430188-0.003305098455530.09546930135230.002144245972650.0883879166036-0.004233331715650.005164848261330.0928774268858-0.002763937327460.08831022631227.6259956590411.486749365213.1875713435
60.08043665337260.01225207133890.02883456714090.1325543013550.01051111128010.1114509250840.09458582971710.0437995422225-0.0280449535444-0.0693727394383-0.06582312012860.02037395781190.0563924813932-0.03663608432230.003405691423470.0992322000867-0.00394249031072-0.005279153034430.1003130566010.003198960883130.101480878926-6.840795213897.74148455116.92603866041
70.3227772052820.0232994717907-0.2364383002230.1741414225160.07433406150450.6166409421830.05013908124910.0186898017660.2114521054480.008773946692680.04750036798910.283076067534-0.287176629691-0.2010383388950.01560685159450.115467048680.0235176993649-0.007971354548310.1358138320620.007630709619940.139495441031-13.072214089118.40386460499.3113714225
80.399104581371-0.1336713772680.2478804713040.431456009906-0.2744410283340.4209883702520.09907713442370.0236286472169-0.1328901106370.00640231911031-0.08729088607440.04611187177060.164595516270.04016154080830.009212537797250.1151100972820.00610410336566-0.003439198822870.1024101508380.0009944319281160.102796926916-4.046668188123.62958941421.9010397029
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 106 )
3X-RAY DIFFRACTION3chain 'A' and (resid 107 through 126 )
4X-RAY DIFFRACTION4chain 'A' and (resid 127 through 164 )
5X-RAY DIFFRACTION5chain 'A' and (resid 165 through 177 )
6X-RAY DIFFRACTION6chain 'A' and (resid 178 through 187 )
7X-RAY DIFFRACTION7chain 'A' and (resid 188 through 197 )
8X-RAY DIFFRACTION8chain 'A' and (resid 198 through 207 )

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