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

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Basic information

Entry
Database: PDB / ID: 7tgu
TitleStructure of Cyclophilin D Peptidyl-Prolyl Isomerase Domain bound to Macrocyclic Inhibitor B1
ComponentsPeptidyl-prolyl cis-trans isomerase F, mitochondrial
KeywordsISOMERASE/ISOMERASE inhibitor / Peptidyl-prolyl isomerase / 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-I44 / Peptidyl-prolyl cis-trans isomerase F, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.21 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 9, 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
X: Peptidyl-prolyl cis-trans isomerase F, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,5502
Polymers17,6661
Non-polymers8841
Water2,288127
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)40.195, 60.141, 66.264
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 F, mitochondrial / PPIase F / Cyclophilin D / CyP-D / CypD / Cyclophilin F / Mitochondrial cyclophilin / CyP-M / Rotamase F


Mass: 17666.150 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) / References: UniProt: P30405, peptidylprolyl isomerase
#2: Chemical ChemComp-I44 / (4S,7S,11R,13E,19S)-N-[2-(2-aminoethoxy)ethyl]-4-[(4-benzoylphenyl)methyl]-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-benzopentaazacyclotetracosine-19-carboxamide


Mass: 884.030 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C50H57N7O8
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 127 / 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: 2.17 Å3/Da / Density % sol: 43.4 % / Description: Blades and tabular, between 0.3-0.5 mm
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.3
Details: 23% 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: 0.97933 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 30, 2019
RadiationMonochromator: Double Crystal Monochromator; Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97933 Å / Relative weight: 1
ReflectionResolution: 1.21→44.534 Å / Num. obs: 43493 / % possible obs: 87.8 % / Redundancy: 10.8 % / Biso Wilson estimate: 11.42 Å2 / CC1/2: 1 / CC star: 1 / Rmerge(I) obs: 0.051 / Rpim(I) all: 0.015 / Rrim(I) all: 0.053 / Net I/σ(I): 23
Reflection shellResolution: 1.21→1.232 Å / Redundancy: 2.6 % / Rmerge(I) obs: 0.428 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 799 / CC1/2: 0.766 / CC star: 0.951 / Rpim(I) all: 0.317 / Rrim(I) all: 0.538 / % possible all: 33.4

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Processing

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

2bit


Resolution: 1.21→44.53 Å / SU ML: 0.0933 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 16.1107
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1604 2108 4.85 %
Rwork0.1513 41381 -
obs0.1518 43489 87.74 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 15.3 Å2
Refinement stepCycle: LAST / Resolution: 1.21→44.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1229 0 65 127 1421
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00771370
X-RAY DIFFRACTIONf_angle_d1.07641852
X-RAY DIFFRACTIONf_chiral_restr0.0819195
X-RAY DIFFRACTIONf_plane_restr0.0071242
X-RAY DIFFRACTIONf_dihedral_angle_d20.3353197
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.21-1.240.2397600.21471082X-RAY DIFFRACTION35.42
1.24-1.270.1941780.19731576X-RAY DIFFRACTION50.71
1.27-1.30.19711040.18362026X-RAY DIFFRACTION65.52
1.3-1.340.20281260.17942417X-RAY DIFFRACTION77.98
1.34-1.390.19591250.16632770X-RAY DIFFRACTION88.24
1.39-1.440.17581330.15833000X-RAY DIFFRACTION95.69
1.44-1.490.1831620.14183102X-RAY DIFFRACTION100
1.49-1.560.13731650.13373115X-RAY DIFFRACTION100
1.56-1.640.14221640.12993125X-RAY DIFFRACTION99.97
1.64-1.750.15511930.13773110X-RAY DIFFRACTION99.97
1.75-1.880.14571530.14553141X-RAY DIFFRACTION100
1.88-2.070.16191570.14493172X-RAY DIFFRACTION100
2.07-2.370.15531690.14133169X-RAY DIFFRACTION100
2.37-2.990.15141630.15763218X-RAY DIFFRACTION100
2.99-44.530.16371560.1573358X-RAY DIFFRACTION99.63
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)
11.44038036349-0.4135710169410.2590156314141.46614030251-0.4737323467941.12899706652-0.055585812927-0.179840590985-0.155944190310.0922293515580.031373765730.03412789434740.1273654478090.02367101466880.01192798462630.08869483811290.0178432027340.02125064635910.09440900848040.02210373026110.07075260946237.4332749295762.760467862673.5508193817
23.53828004679-0.861239714843-0.5255921905961.64378366460.3077226486191.04864821261-0.0474282382476-0.00895983106965-0.3363192173650.006452108912170.01041595638180.1221387821710.1278754994420.01673971623940.05793866951130.110614129322-0.00651628190231-0.005095395257520.08573415448450.0006910759239880.1325077760598.1160857773555.987594243965.0742322363
31.42570798735-0.943893923552-0.5097853460694.168212471071.839497035750.819860834725-0.02614755872420.296965946531-0.301165690363-0.00412185195748-0.2348748994420.4288789503340.0916857933494-0.19113647550.2323183494180.10342266035-0.0143057115096-0.0007003815869560.146830923702-0.05041020140550.1707974896010.66779954125159.143216004459.1132210113
41.197109979020.00215840543759-0.03437742089851.47259570011-0.1591240919360.9642710487730.02427464707920.110286795997-0.00936393393011-0.0687111360971-0.0456749653099-0.09302326377050.05572933221420.05295008149380.02056221427060.08347664253070.007536803652810.007540052487590.0951079506560.00208140366520.075651605581714.735085988366.016493967661.3983157737
51.94951774568-0.2340237907640.5411356905012.63633344433-0.6729464952921.13455783276-0.068770532984-0.0742948797238-0.007287196292270.08866615967280.0192292195144-0.111726303206-0.03482467957650.1338354771240.08190898591480.05325512311790.0143874791436-0.000404814309640.08851637800840.00470593166060.071965025872515.502505768166.455028332767.0022904844
63.62457470260.208481770371-1.151284927617.253738306432.830576754763.28143288392-0.180414293042-0.229682446068-0.2898426358750.3125392084540.214776726344-0.2001754160360.2443685285520.154852642972-0.0185851266180.1862254008860.05250026991150.003522362675890.1487164143770.04374482766860.16773690829418.848627277351.568004127372.0686202295
72.66467072892-1.46155919803-1.571643312052.544199262861.105182445252.44810982259-0.250546138367-0.0634524529304-0.5874775327320.2396076882260.07804869794360.2209568586550.4054749511840.06512956418450.148653457490.1383185240880.008607176279270.01164964052920.1064500244850.01730907696890.2264276487239.8265548059150.854384630169.019202978
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'X' and (resid 3 through 42 )
2X-RAY DIFFRACTION2chain 'X' and (resid 43 through 65 )
3X-RAY DIFFRACTION3chain 'X' and (resid 66 through 85 )
4X-RAY DIFFRACTION4chain 'X' and (resid 86 through 123 )
5X-RAY DIFFRACTION5chain 'X' and (resid 124 through 136 )
6X-RAY DIFFRACTION6chain 'X' and (resid 137 through 146 )
7X-RAY DIFFRACTION7chain 'X' and (resid 147 through 165 )

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