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

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Basic information

Entry
Database: PDB / ID: 7thd
TitleStructure of Cyclophilin D Peptidyl-Prolyl Isomerase Domain bound to Macrocyclic Inhibitor B52
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-I4V / Peptidyl-prolyl cis-trans isomerase F, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.16 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)18,5672
Polymers17,5951
Non-polymers9721
Water2,936163
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)38.408, 67.032, 69.324
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-I4V / [(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)methyl]propanedioic acid


Mass: 972.092 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C53H61N7O11 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 163 / 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: 2.39 Å3/Da / Density % sol: 48.6 % / Description: Bladed, tabular, roughly 0.3-0.5 mm in length
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 15% 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: 1.16→25.73 Å / Num. obs: 62319 / % possible obs: 99 % / Redundancy: 12.9 % / Biso Wilson estimate: 9.65 Å2 / CC1/2: 0.995 / CC star: 1 / Rmerge(I) obs: 0.03362 / Rpim(I) all: 0.02377 / Rrim(I) all: 0.03362 / Net I/σ(I): 13.5
Reflection shellResolution: 1.16→1.19 Å / Redundancy: 9.3 % / Rmerge(I) obs: 0.595 / Mean I/σ(I) obs: 2.9 / Num. unique obs: 4063 / CC1/2: 0.921 / CC star: 0.987 / Rpim(I) all: 0.1625 / Rrim(I) all: 0.2297 / % possible all: 88.5

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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: 1.16→25.73 Å / SU ML: 0.0713 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 13.1734
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1516 2011 3.23 %
Rwork0.1357 60232 -
obs0.1362 62243 98.98 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 12.43 Å2
Refinement stepCycle: LAST / Resolution: 1.16→25.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1236 0 71 164 1471
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01121348
X-RAY DIFFRACTIONf_angle_d1.32661819
X-RAY DIFFRACTIONf_chiral_restr0.0909191
X-RAY DIFFRACTIONf_plane_restr0.0116236
X-RAY DIFFRACTIONf_dihedral_angle_d19.266264
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.16-1.190.19431290.18693750X-RAY DIFFRACTION87.72
1.19-1.220.16181340.15844264X-RAY DIFFRACTION98.79
1.22-1.260.1761490.14834241X-RAY DIFFRACTION99.64
1.26-1.30.16621390.1444305X-RAY DIFFRACTION99.84
1.3-1.340.13061500.13854299X-RAY DIFFRACTION99.91
1.34-1.40.14861460.13084279X-RAY DIFFRACTION99.95
1.4-1.460.14191370.1274325X-RAY DIFFRACTION99.96
1.46-1.540.1071470.12014317X-RAY DIFFRACTION99.93
1.54-1.630.11161390.11844321X-RAY DIFFRACTION100
1.63-1.760.12551500.1194360X-RAY DIFFRACTION100
1.76-1.940.13121450.11884350X-RAY DIFFRACTION100
1.94-2.220.13151470.11954377X-RAY DIFFRACTION100
2.22-2.790.14241430.13034436X-RAY DIFFRACTION100
2.79-25.730.19481560.15534608X-RAY DIFFRACTION99.85
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)
10.09177280634210.0247950024781-0.1658634538841.132924155840.003505129161890.9917021521010.003374463102340.0295237352901-0.1195062708220.0262767799463-0.001229712943760.06021580820660.0478522520151-0.0340843168187-0.0006511263467640.07281216122440.003275835661070.007680377579260.0799075481533-0.0003944450612130.100424316475-3.400148023833.2191899385417.1262795643
20.2003085877910.04246632056570.02943424594620.409954715809-0.03563201079560.2720956509030.00855083650761-0.0477551479377-0.0940512313310.108002421654-0.00373514239263-0.1765976439980.04968813359890.1380313274710.0002615109908710.07530683530590.00306797710151-0.005490620757590.101644558672-0.003220928847420.1023849226918.632456481239.5360552266224.6729786255
30.3451394744080.003253498209360.05888854044610.3771132619750.2590599936640.255805901050.0259470307736-0.009063035034220.02033823327810.0128076812246-0.0119827221480.0501428255789-0.0323296145849-0.0858109422988-0.003441481407050.073396707927-0.001212361869230.005841651846130.0748047505897-0.005961402719350.0683576495513-4.3450616049114.588778598718.3361154488
40.0689199453885-0.05353363697410.07119220115280.36999895556-0.1061917770130.379040862109-0.0569228987557-0.09320287315090.06026839624830.1329401009440.02429836784950.0203014973121-0.0957523730264-0.0365533218112-0.0006107477228150.106172081-0.0005755476227450.001129517141290.091949776421-0.005927190228180.079417093033-0.75247795003720.23214711626.9085169149
50.733035544964-0.08225802666660.284099610680.6165777323120.2874243207430.422740523428-0.005312061124140.08958136409050.063956374578-0.09547676364870.0218389199084-0.0805372498252-0.1696150578510.1366540736190.0005110618783220.0915771862191-0.01885823577760.007921405740250.08678346126850.004802054115120.08457501840337.1778914448617.993534859713.9971652461
60.618806413993-0.159164855360.07909858054790.1117410728090.006020522168130.322977290798-0.01517428783240.0713195032216-0.0704518614303-0.1462104325540.0718269952169-0.155319338051-0.04181762904060.133468022517-0.001907722151020.0855693508343-0.01124412605660.01365996621270.0884408136793-0.002600778370670.08598250626427.5747535627212.200544900113.5018730419
70.475592418304-0.2115939720410.0289155152830.5197874402460.09338973431820.2462635052970.09410225643880.03617371973350.0274705299083-0.116370470701-0.06321870326410.006790702089180.0438324384969-0.0558688742993-0.0004282631851740.0879475068587-0.00143241911487-0.00420289689380.09834832898680.001543251217320.102462348282-6.651294059987.948997181216.95259932077
81.222517469230.684946528144-0.7499169278730.9132015162170.5165230292852.341153458870.036482728969-0.007802588454310.238170303003-0.06825359881460.07956197301890.329488356616-0.298155504161-0.2029214918540.0125431299310.08411715221050.0513700311311-0.0089931080720.1418362622710.01081945966350.13488261255-13.072761596118.33537433279.28806385075
90.177112439480.233504844636-0.05496004838480.361002533890.03574065437240.3459283537070.116804003388-0.0189371606915-0.1470998333620.0734884382085-0.08685502508670.0300629427440.1703388528350.0205741958467-0.002554962424870.1088197120980.00255933269974-0.001821261669430.09555220866460.003453877042330.103108208405-4.015708143533.7187424594222.0514766707
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 126 )
5X-RAY DIFFRACTION5chain 'A' and (resid 127 through 164 )
6X-RAY DIFFRACTION6chain 'A' and (resid 165 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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