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

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Basic information

Entry
Database: PDB / ID: 7tgs
TitleStructure of Cyclophilin D Peptidyl-Prolyl Isomerase Domain bound to Macrocyclic Inhibitor JOMBt
ComponentsPeptidyl-prolyl cis-trans isomerase F, mitochondrial
KeywordsISOMERASE / Peptidyl-prolyl isomerase / 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 / mitochondrial depolarization / cellular response to arsenic-containing substance / negative regulation of ATP-dependent activity / 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 / mitochondrial depolarization / cellular response to arsenic-containing substance / negative regulation of ATP-dependent activity / negative regulation of oxidative phosphorylation / regulation of mitochondrial membrane permeability / cyclosporin A binding / negative regulation of release of cytochrome c from mitochondria / apoptotic mitochondrial changes / necroptotic process / negative regulation of intrinsic apoptotic signaling pathway / protein peptidyl-prolyl isomerization / cellular response to calcium ion / peptidylprolyl isomerase / peptidyl-prolyl cis-trans isomerase activity / response to ischemia / 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-I3Q / Peptidyl-prolyl cis-trans isomerase F, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 Å
AuthorsRangwala, A.M. / 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

Downloads & links

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Assembly

Deposited unit
X: Peptidyl-prolyl cis-trans isomerase F, mitochondrial
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,3322
Polymers17,6521
Non-polymers6801
Water1,62190
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)38.505, 57.879, 78.010
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: 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 (E. coli) / References: UniProt: P30405, peptidylprolyl isomerase
#2: Chemical ChemComp-I3Q / (4S,7R,11S,13E,19S)-N-[2-(2-aminoethoxy)ethyl]-4-[(furan-2-yl)methyl]-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 / Macrocyclic Inhibitor JOMBt


Mass: 679.763 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H45N7O8
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 90 / 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: 2.43 Å3/Da / Density % sol: 49.48 % / Description: Bladed and tabular morphology, ranging from
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.3
Details: 19% PEG 3350 0.5 M KH2PO4 1:3 ratio of protein to inhibitor 1 uL of protein:inhibitor complex was mixed with 1 uL of 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: 1.75→46.48 Å / Num. obs: 17266 / % possible obs: 94.2 % / Redundancy: 12.7 % / Biso Wilson estimate: 22.3 Å2 / CC1/2: 0.996 / CC star: 0.999 / Rmerge(I) obs: 0.136 / Rpim(I) all: 0.04 / Rrim(I) all: 0.142 / Net I/σ(I): 12.5
Reflection shellResolution: 1.75→1.776 Å / Redundancy: 13.5 % / Rmerge(I) obs: 1.195 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 869 / CC1/2: 0.772 / CC star: 0.954 / Rpim(I) all: 0.333 / Rrim(I) all: 0.142 / % possible all: 99.9

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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: 1.75→46.48 Å / SU ML: 0.1142 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 17.6618
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1842 855 4.95 %
Rwork0.1702 16411 -
obs0.1709 17266 94.2 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 22.3 Å2
Refinement stepCycle: LAST / Resolution: 1.75→46.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1240 0 49 90 1379
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00681328
X-RAY DIFFRACTIONf_angle_d0.98611789
X-RAY DIFFRACTIONf_chiral_restr0.0541190
X-RAY DIFFRACTIONf_plane_restr0.0051233
X-RAY DIFFRACTIONf_dihedral_angle_d22.8516191
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.75-1.850.20781310.18172803X-RAY DIFFRACTION98.49
1.86-20.22561260.16682346X-RAY DIFFRACTION82.13
2-2.20.16661560.14122816X-RAY DIFFRACTION99.2
2.2-2.520.1681280.14772484X-RAY DIFFRACTION85.64
2.52-3.170.16231490.15062918X-RAY DIFFRACTION99.61
3.17-46.480.1971650.19383044X-RAY DIFFRACTION99.81
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)
12.336125668791.426962656480.04062019462843.35885685315-0.1522807801752.794495726420.123415700334-0.292218732569-0.3733562232960.04724107089470.029426712772-0.02247714695920.316589168871-0.270451405868-0.1553664080880.1534126657770.01444029932560.03189477356940.1324518694010.007027996266210.12993597759251.7094373578-0.36758716418593.3725544799
22.42744422136-1.27317230971-1.490505436792.60307505059-1.880498923794.645233313760.0296761850667-0.2263414168320.07016722229120.2300916317610.08515421801890.19406493084-0.0419453468275-0.0348731868383-0.0930937616060.1789088313960.03664026053880.02007539189790.18591356881-0.01253296237570.15245166113354.47906025299.1886588621499.8978214483
32.37752207925-0.0137643426467-2.223736526941.285124741891.510293450937.989825184190.002755745431730.01110852919870.0742767452367-0.03889053749090.04570931767010.01679411184710.10236964133-0.146803086399-0.06789057481680.1450253215060.0335380337219-0.0003387352712830.1439392412390.01120129993790.1955404214849.89711908868.2826575928787.0072869149
41.290406370680.4757561739130.440519195290.8170962909530.1724494512452.42628015716-0.0209217853105-0.04337464529030.0467690927385-0.03262398224130.0208062093072-0.0483005833572-0.09467527802040.04733830658760.008607150100480.1543012727230.004053768599520.01342448401280.1502504810620.005544958910880.17116855486858.564783105912.105176305488.7590566407
55.353371485522.695427498472.202518667857.693294214812.693242775982.978927454820.181169316726-0.0920144125507-0.1207597840090.501222456799-0.174069187376-0.08388181128290.1606313729360.0543322178940.0702750880060.0965612261480.06130324758120.02793937613810.144805097780.01434154890370.11150918124861.88261305984.2327503705690.1041958827
68.14453587724-3.765953031743.876539258479.7123196715-5.692637181963.859933357310.01182835904640.0954299397108-0.275199300316-0.2521959437810.07428245350440.1384956720230.85377017502-0.134009871693-0.05676137208560.248455416683-0.009004285146990.02219074179460.17265417738-0.03625494238250.19247970174851.2460442996-3.3957988243380.6394746953
71.857973890761.86729488623-1.5566497562.33945603399-3.059037537738.32557722622-0.07112004820850.0693803478284-0.0947838146379-0.1850055917130.223265903156-0.1779462952710.0359204426988-0.474551294749-0.1347017691840.1505861408660.0181161359196-0.02091865769080.212475424709-0.01194840556310.16263968265246.9425701426.6087682406373.8613051749
84.87628445478-2.096794789064.384930156062.78853957264-2.880175452244.41533172525-0.102902370519-0.393489798135-0.002985411435980.1578028518580.1931500634970.2070759775580.00174836824874-0.534800257553-0.05549213640560.178793817898-0.009813962651120.03900772614510.182640737571-0.002505221435180.19866711604746.17172647611.402541531694.7641409341
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'X' and (resid 2 through 29 )
2X-RAY DIFFRACTION2chain 'X' and (resid 30 through 41 )
3X-RAY DIFFRACTION3chain 'X' and (resid 42 through 64 )
4X-RAY DIFFRACTION4chain 'X' and (resid 65 through 122 )
5X-RAY DIFFRACTION5chain 'X' and (resid 123 through 135 )
6X-RAY DIFFRACTION6chain 'X' and (resid 136 through 145 )
7X-RAY DIFFRACTION7chain 'X' and (resid 146 through 155 )
8X-RAY DIFFRACTION8chain 'X' and (resid 156 through 165 )

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