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- PDB-1mf8: Crystal Structure of human calcineurin complexed with cyclosporin... -

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Basic information

Entry
Database: PDB / ID: 1mf8
TitleCrystal Structure of human calcineurin complexed with cyclosporin A and human cyclophilin
Components
  • CALCINEURIN B SUBUNIT ISOFORM 1
  • CALMODULIN-DEPENDENT CALCINEURIN A SUBUNIT, ALPHA ISOFORM
  • CYCLOSPORIN A
  • PEPTIDYL-PROLYL CIS-TRANS ISOMERASE A
KeywordsHYDROLASE/ISOMERASE/IMMUNOSUPPRESSANT / HYDROLASE-ISOMERASE-IMMUNOSUPPRESSANT COMPLEX / CALCINEURIN-CYCLOPHILIN-CYCLOSPORIN COMPLEX / CYCLOSPORIN A / IMMUNOSUPPRESSANT / HYDROLASE / ISOMERASE
Function / homology
Function and homology information


negative regulation of angiotensin-activated signaling pathway / regulation of cell proliferation involved in kidney morphogenesis / calcium-dependent protein serine/threonine phosphatase regulator activity / positive regulation of glomerulus development / negative regulation of calcium ion import across plasma membrane / calcium-dependent protein serine/threonine phosphatase activity / protein serine/threonine phosphatase complex / negative regulation of signaling / positive regulation of saliva secretion / positive regulation of cardiac muscle hypertrophy in response to stress ...negative regulation of angiotensin-activated signaling pathway / regulation of cell proliferation involved in kidney morphogenesis / calcium-dependent protein serine/threonine phosphatase regulator activity / positive regulation of glomerulus development / negative regulation of calcium ion import across plasma membrane / calcium-dependent protein serine/threonine phosphatase activity / protein serine/threonine phosphatase complex / negative regulation of signaling / positive regulation of saliva secretion / positive regulation of cardiac muscle hypertrophy in response to stress / positive regulation of calcium ion import across plasma membrane / calmodulin-dependent protein phosphatase activity / calcineurin complex / positive regulation of connective tissue replacement / negative regulation of dendrite morphogenesis / calcineurin-mediated signaling / slit diaphragm / peptidyl-serine dephosphorylation / lung epithelial cell differentiation / calcineurin-NFAT signaling cascade / renal filtration / skeletal muscle tissue regeneration / regulation of synaptic vesicle cycle / transition between fast and slow fiber / positive regulation of calcineurin-NFAT signaling cascade / myelination in peripheral nervous system / negative regulation of protein K48-linked ubiquitination / negative regulation of viral life cycle / regulation of apoptotic signaling pathway / cell adhesion molecule production / lipid droplet organization / heparan sulfate binding / regulation of viral genome replication / cardiac muscle hypertrophy in response to stress / positive regulation of osteoclast differentiation / regulation of postsynaptic neurotransmitter receptor internalization / leukocyte chemotaxis / endothelial cell activation / parallel fiber to Purkinje cell synapse / virion binding / dendrite morphogenesis / Basigin interactions / negative regulation of stress-activated MAPK cascade / cyclosporin A binding / myosin phosphatase activity / CLEC7A (Dectin-1) induces NFAT activation / branching involved in blood vessel morphogenesis / postsynaptic modulation of chemical synaptic transmission / extrinsic component of plasma membrane / protein serine/threonine phosphatase activity / protein-serine/threonine phosphatase / Minus-strand DNA synthesis / Plus-strand DNA synthesis / Uncoating of the HIV Virion / positive regulation of activated T cell proliferation / Early Phase of HIV Life Cycle / Integration of provirus / positive regulation of endocytosis / APOBEC3G mediated resistance to HIV-1 infection / Calcineurin activates NFAT / viral release from host cell / positive regulation of cell adhesion / DARPP-32 events / Activation of BAD and translocation to mitochondria / epidermis development / epithelial to mesenchymal transition / phosphatase binding / Binding and entry of HIV virion / negative regulation of insulin secretion / positive regulation of viral genome replication / multicellular organismal response to stress / positive regulation of osteoblast differentiation / protein peptidyl-prolyl isomerization / skeletal muscle fiber development / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / dephosphorylation / positive regulation of protein dephosphorylation / keratinocyte differentiation / response to amphetamine / T cell activation / excitatory postsynaptic potential / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / activation of protein kinase B activity / hippocampal mossy fiber to CA3 synapse / FCERI mediated Ca+2 mobilization / protein dephosphorylation / neutrophil chemotaxis / negative regulation of protein phosphorylation / peptidylprolyl isomerase / peptidyl-prolyl cis-trans isomerase activity / positive regulation of protein secretion / cellular response to glucose stimulus / Assembly Of The HIV Virion / negative regulation of protein kinase activity / wound healing / Schaffer collateral - CA1 synapse / modulation of chemical synaptic transmission / Budding and maturation of HIV virion / neuron differentiation / platelet activation
Similarity search - Function
Calcineurin B protein / PP2B, metallophosphatase domain / PP2B / Serine/threonine specific protein phosphatases signature. / Protein phosphatase 2A homologues, catalytic domain. / Serine/threonine-specific protein phosphatase/bis(5-nucleosyl)-tetraphosphatase / Metallo-dependent phosphatases / Purple Acid Phosphatase; chain A, domain 2 / Cyclophilin-like / Cyclophilin ...Calcineurin B protein / PP2B, metallophosphatase domain / PP2B / Serine/threonine specific protein phosphatases signature. / Protein phosphatase 2A homologues, catalytic domain. / Serine/threonine-specific protein phosphatase/bis(5-nucleosyl)-tetraphosphatase / Metallo-dependent phosphatases / Purple Acid Phosphatase; chain A, domain 2 / Cyclophilin-like / Cyclophilin / Cyclophilin-type peptidyl-prolyl cis-trans isomerase / Calcineurin-like phosphoesterase domain, ApaH type / Calcineurin-like phosphoesterase / 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 / Metallo-dependent phosphatase-like / Cyclophilin-like domain superfamily / EF-hand / Recoverin; domain 1 / EF-hand domain pair / EF-hand, calcium binding motif / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. / EF-hand calcium-binding domain profile. / EF-hand domain / 4-Layer Sandwich / EF-hand domain pair / Beta Barrel / Orthogonal Bundle / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Cyclosporin A / PHOSPHATE ION / : / Peptidyl-prolyl cis-trans isomerase A / Calcineurin subunit B type 1 / Protein phosphatase 3 catalytic subunit alpha
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
TOLYPOCLADIUM INFLATUM (fungus)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.1 Å
AuthorsJin, L. / Harrison, S.C.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2002
Title: Crystal Structure of Human Calcineurin Complexed with Cyclosporin a and Human Cyclophilin
Authors: Jin, L. / Harrison, S.C.
History
DepositionAug 9, 2002Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 16, 2002Provider: repository / Type: Initial release
Revision 1.1Jun 14, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Jul 27, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary
Revision 1.4Dec 12, 2012Group: Other

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: CALMODULIN-DEPENDENT CALCINEURIN A SUBUNIT, ALPHA ISOFORM
B: CALCINEURIN B SUBUNIT ISOFORM 1
C: PEPTIDYL-PROLYL CIS-TRANS ISOMERASE A
D: CYCLOSPORIN A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)81,6069
Polymers81,3514
Non-polymers2555
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7390 Å2
ΔGint-91 kcal/mol
Surface area28770 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.949, 108.334, 112.841
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 3 types, 3 molecules ABC

#1: Protein CALMODULIN-DEPENDENT CALCINEURIN A SUBUNIT, ALPHA ISOFORM / SERINE/THREONINE PROTEIN PHOSPHATASE 2B CATALYTIC SUBUNIT ALPHA ISOFORM / CAM-PRP CATALYTIC SUBUNIT


Mass: 42770.637 Da / Num. of mol.: 1 / Fragment: TRUNCATED FORM (RESIDUES 20-392)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PETCN ALPHA / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) PLYSS
References: UniProt: Q08209, protein-serine/threonine phosphatase
#2: Protein CALCINEURIN B SUBUNIT ISOFORM 1 / PROTEIN PHOSPHATASE 2B REGULATORY SUBUNIT 1 / PROTEIN PHOSPHATASE 3 REGULATORY SUBUNIT B ALPHA ISOFORM 1


Mass: 19322.904 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PETCN ALPHA / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) PLYSS
References: UniProt: P63098, protein-serine/threonine phosphatase
#3: Protein PEPTIDYL-PROLYL CIS-TRANS ISOMERASE A / PPIASE / ROTAMASE / CYCLOPHILIN A


Mass: 18036.504 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PET3A.CYPA / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) CODONPLUS RIL / References: UniProt: P62937, peptidylprolyl isomerase

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Protein/peptide , 1 types, 1 molecules D

#4: Protein/peptide CYCLOSPORIN A / CYCLOSPORINE / CICLOSPORIN / CICLOSPORINE


Type: Cyclic peptide / Class: Immunosuppressant / Mass: 1220.625 Da / Num. of mol.: 1 / Source method: obtained synthetically
Details: CYCLOSPORIN IS A CYCLIC UNDECAPEPTIDE. CYCLIZATION IS ACHIEVED BY LINKING THE N- AND THE C- TERMINI.
Source: (synth.) TOLYPOCLADIUM INFLATUM (fungus) / References: NOR: NOR00033, Cyclosporin A

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Non-polymers , 2 types, 5 molecules

#5: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#6: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca

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Details

Compound detailsCYCLOSPORIN IS A CYCLIC UNDECAPEPTIDE. HERE, CYCLOSPORIN A IS REPRESENTED BY THE SEQUENCE (SEQRES)

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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: 2.6 Å3/Da / Density % sol: 46 %
Crystal growpH: 4.6
Details: 12% PEG 4000, 5MM POTASSIUM PHOSPHATE, 75MM SODIUM CITRATE, 15% GLYCEROL, 5MM TRIS, PH 4.6, MICROBATCH, TEMPERATURE 292K
Crystal grow
*PLUS
Temperature: 19 ℃ / Method: batch method
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDChemical formulaDetails
15 mg/mlprotein11
2150 mMNa3Citr11
310 mM11KH2PO4
424 %PEG400011
530 %glycerol11pH4.6

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CHESS / Beamline: F1 / Wavelength: 0.91611
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Mar 12, 2002
RadiationMonochromator: SI 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91611 Å / Relative weight: 1
ReflectionResolution: 3.1→15 Å / Num. obs: 14195 / % possible obs: 95.6 % / Observed criterion σ(I): 0 / Redundancy: 5.3 % / Rsym value: 0.077 / Net I/σ(I): 19.3
Reflection shellResolution: 3.1→3.21 Å / Mean I/σ(I) obs: 3.3 / Rsym value: 0.37 / % possible all: 81.7
Reflection
*PLUS
Lowest resolution: 15 Å / Rmerge(I) obs: 0.077
Reflection shell
*PLUS
Highest resolution: 3.1 Å / % possible obs: 81.7 % / Rmerge(I) obs: 0.377

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Processing

Software
NameClassification
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1AUI AND 2RMA

1aui

2rma


Resolution: 3.1→15 Å / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: ENGH & HUBER
RfactorNum. reflection% reflectionSelection details
Rfree0.3 1052 -RANDOM
Rwork0.25 ---
obs0.25 14195 95.6 %-
Refinement stepCycle: LAST / Resolution: 3.1→15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5513 0 9 0 5522
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.01
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.5
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it
X-RAY DIFFRACTIONc_mcangle_it
X-RAY DIFFRACTIONc_scbond_it
X-RAY DIFFRACTIONc_scangle_it
Refinement
*PLUS
Lowest resolution: 15 Å / Rfactor obs: 0.26 / Rfactor Rfree: 0.3 / Rfactor Rwork: 0.255
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Type: c_bond_d / Dev ideal: 0.01
LS refinement shell
*PLUS
Highest resolution: 3.1 Å / Lowest resolution: 3.21 Å / Rfactor Rfree: 0.45 / Rfactor Rwork: 0.409

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