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- PDB-1m63: Crystal structure of calcineurin-cyclophilin-cyclosporin shows co... -

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Basic information

Entry
Database: PDB / ID: 1m63
TitleCrystal structure of calcineurin-cyclophilin-cyclosporin shows common but distinct recognition of immunophilin-drug complexes
Components
  • CALCINEURIN B SUBUNIT ISOFORM 1
  • CYCLOSPORIN ACiclosporin
  • PEPTIDYL-PROLYL CIS-TRANS ISOMERASE A
  • SERINE/THREONINE PROTEIN PHOSPHATASE 2B CATALYTIC SUBUNIT, ALPHA ISOFORMSerine/threonine-specific protein kinase
KeywordsHYDROLASE/ISOMERASE/IMMUNOSUPPRESSANT / HYDROLASE-ISOMERASE-IMMUNOSUPPRESSANT COMPLEX / IMMUNOPHILIN / CALCINEURIN / CYCLOSPORIN A / IMMUNOSUPPRESSANT / CYCLOPHILIN
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 / slit diaphragm / calcineurin complex / positive regulation of connective tissue replacement / negative regulation of dendrite morphogenesis / calcineurin-mediated signaling / peptidyl-serine dephosphorylation / lung epithelial cell differentiation / calcineurin-NFAT signaling cascade / skeletal muscle tissue regeneration / renal filtration / regulation of synaptic vesicle cycle / positive regulation of calcineurin-NFAT signaling cascade / myelination in peripheral nervous system / transition between fast and slow fiber / 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 / negative regulation of stress-activated MAPK cascade / endothelial cell activation / dendrite morphogenesis / parallel fiber to Purkinje cell synapse / virion binding / Basigin interactions / cyclosporin A binding / myosin phosphatase activity / branching involved in blood vessel morphogenesis / protein serine/threonine phosphatase activity / CLEC7A (Dectin-1) induces NFAT activation / extrinsic component of plasma membrane / postsynaptic modulation of chemical synaptic transmission / positive regulation of endocytosis / protein-serine/threonine phosphatase / positive regulation of activated T cell proliferation / Minus-strand DNA synthesis / Plus-strand DNA synthesis / Uncoating of the HIV Virion / Early Phase of HIV Life Cycle / Integration of provirus / APOBEC3G mediated resistance to HIV-1 infection / Calcineurin activates NFAT / DARPP-32 events / positive regulation of cell adhesion / viral release from host cell / Activation of BAD and translocation to mitochondria / epithelial to mesenchymal transition / negative regulation of insulin secretion / epidermis development / multicellular organismal response to stress / phosphatase binding / positive regulation of osteoblast differentiation / positive regulation of viral genome replication / Binding and entry of HIV virion / skeletal muscle fiber development / protein peptidyl-prolyl isomerization / dephosphorylation / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / positive regulation of protein dephosphorylation / keratinocyte differentiation / response to amphetamine / excitatory postsynaptic potential / hippocampal mossy fiber to CA3 synapse / Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation / activation of protein kinase B activity / T cell activation / 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 / G1/S transition of mitotic cell cycle / negative regulation of protein kinase activity / sarcolemma / modulation of chemical synaptic transmission / Schaffer collateral - CA1 synapse / wound healing / Budding and maturation of HIV virion
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 / Cyclophilin-like domain superfamily / Metallo-dependent phosphatase-like / 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 / : / : / 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: 2.8 Å
AuthorsHuai, Q. / Kim, H.-Y. / Liu, Y. / Zhao, Y. / Mondragon, A. / Liu, J.O. / Ke, H.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2002
Title: Crystal Structure of Calcineurin-Cyclophilin-Cyclosporin Shows Common But Distinct Recognition of Immunophilin-Drug Complexes
Authors: Huai, Q. / Kim, H.-Y. / Liu, Y. / Zhao, Y. / Mondragon, A. / Liu, J.O. / Ke, H.
History
DepositionJul 12, 2002Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 25, 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
Revision 1.5Nov 1, 2017Group: Derived calculations / Category: pdbx_struct_assembly / Item: _pdbx_struct_assembly.method_details
Revision 1.6Jul 21, 2021Group: Data collection / Derived calculations / Refinement description
Category: pdbx_struct_conn_angle / refine ...pdbx_struct_conn_angle / refine / struct_biol / struct_conn / struct_conn_type / struct_site
Item: _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id ..._pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _refine.ls_percent_reflns_obs / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn_type.id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.7Apr 3, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: SERINE/THREONINE PROTEIN PHOSPHATASE 2B CATALYTIC SUBUNIT, ALPHA ISOFORM
B: CALCINEURIN B SUBUNIT ISOFORM 1
C: PEPTIDYL-PROLYL CIS-TRANS ISOMERASE A
D: CYCLOSPORIN A
E: SERINE/THREONINE PROTEIN PHOSPHATASE 2B CATALYTIC SUBUNIT, ALPHA ISOFORM
F: CALCINEURIN B SUBUNIT ISOFORM 1
G: PEPTIDYL-PROLYL CIS-TRANS ISOMERASE A
H: CYCLOSPORIN A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)163,21320
Polymers162,6508
Non-polymers56312
Water0
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area17630 Å2
ΔGint-270 kcal/mol
Surface area58150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)108.657, 108.657, 316.590
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212
DetailsOne complex of CN-CyPA-CsA is a biological unit

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Components

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Protein , 3 types, 6 molecules AEBFCG

#1: Protein SERINE/THREONINE PROTEIN PHOSPHATASE 2B CATALYTIC SUBUNIT, ALPHA ISOFORM / Serine/threonine-specific protein kinase / CALMODULIN-DEPENDENT CALINEURIN A SUBUNIT / ALPHA ISOFORM / CAM-PRP SUBUNIT


Mass: 42876.148 Da / Num. of mol.: 2 / Fragment: RESIDUES 1-372
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Gene: CNA ALPHA / Plasmid: PET-CNA / Production host: ESCHERICHIA COLI BL21 (bacteria) / Strain (production host): BL21
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: 19191.709 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Gene: CNB / Plasmid: PET-CNA / Production host: ESCHERICHIA COLI BL21 (bacteria) / Strain (production host): BL21 / References: UniProt: P63098
#3: Protein PEPTIDYL-PROLYL CIS-TRANS ISOMERASE A / PPIASE / ROTAMASE / CYCLOPHILIN A / CYCLOSPORIN A- BINDING PROTEIN


Mass: 18036.504 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PGEX-GST-CYPA / Production host: ESCHERICHIA COLI BL21 (bacteria) / Strain (production host): BL21 / References: UniProt: P62937, peptidylprolyl isomerase

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Protein/peptide , 1 types, 2 molecules DH

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


Type: Cyclic peptide / Class: ImmunosuppressantImmunosuppressive drug / Mass: 1220.625 Da / Num. of mol.: 2 / 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 , 3 types, 12 molecules

#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#6: Chemical ChemComp-FE / FE (III) ION / Iron


Mass: 55.845 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Fe
#7: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 8 / 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: 2.87 Å3/Da / Density % sol: 57.16 %
Crystal growpH: 6.5
Details: 0.1 M NA CACODYLATE, 0.2 M MGCL2, 13% PEG8000, 2.5% ETHANOL, PH 6.5, VAPOR DIFFUSION, HANGING DROP, TEMPERATURE 295K
Crystal grow
*PLUS
pH: 7.5 / Method: vapor diffusion
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDChemical formulaDetails
115 mg/mlprotein1drop
20.1 M1dropNaCl
320 mMTris-HCl1droppH7.5
41 mM2-mercaptoethanol1drop
52 mM1dropCaCl2
60.1 MHEPES1reservoirpH7.5
71.5 M1reservoirLi2SO4

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 14-BM-C / Wavelength: 1
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Jun 15, 2001
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.8→40 Å / Num. obs: 43551 / % possible obs: 90.9 % / Observed criterion σ(I): -3 / Redundancy: 4.2 % / Rmerge(I) obs: 0.136 / Rsym value: 0.136 / Net I/σ(I): 7.1
Reflection shellResolution: 2.8→2.9 Å / Rmerge(I) obs: 0.326 / Mean I/σ(I) obs: 1.5 / % possible all: 62.9
Reflection
*PLUS
Highest resolution: 2.8 Å / Num. measured all: 183803 / Rmerge(I) obs: 0.136
Reflection shell
*PLUS
% possible obs: 62.9 % / Rmerge(I) obs: 0.326

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Processing

Software
NameClassification
AMoREphasing
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: CNA FROM THE CN-FKBP COMPLEX CYPA FROM THE UNLIGATED STRUCTURE

Resolution: 2.8→40 Å / σ(F): 0 / Stereochemistry target values: ENGH & HUBER
RfactorNum. reflection% reflectionSelection details
Rfree0.322 4151 -10
Rwork0.26 ---
obs0.26 42237 90 %-
Displacement parametersBiso mean: 64.3 Å2
Refinement stepCycle: LAST / Resolution: 2.8→40 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms11173 0 12 0 11185
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONr_bond_refined_d0.013
X-RAY DIFFRACTIONr_angle_refined_deg1.67
Refinement
*PLUS
Highest resolution: 2.8 Å / Lowest resolution: 50 Å / Num. reflection obs: 42377 / Rfactor Rfree: 0.322 / Rfactor Rwork: 0.26
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.013
X-RAY DIFFRACTIONx_angle_d
X-RAY DIFFRACTIONx_angle_deg1.67

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