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- PDB-6tz8: Crystal structure of Cryptococcus neoformans Calceineurin A, Calc... -

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Basic information

Entry
Database: PDB / ID: 6tz8
TitleCrystal structure of Cryptococcus neoformans Calceineurin A, Calcineurin B, and FKBP12 with FK-506
Components
  • Calcineurin subunit B
  • FK506-binding protein 1
  • Serine/threonine-protein phosphatase 2B catalytic subunit A1
KeywordsHydrolase/Isomerase/Calcium Binding / Calcineurin A / CnA / CnB / FKBP12 / FK-506 / Structural Genomics / Seattle Structural Genomics Center for Infectious Disease / SSGCID / Hydrolase-Isomerase-Calcium Binding complex
Function / homology
Function and homology information


mitotic actomyosin contractile ring, intermediate layer / positive regulation of mitotic actomyosin contractile ring contraction / positive regulation of mitotic division septum assembly / fungal-type cell wall organization or biogenesis / protein serine/threonine phosphatase activity => GO:0004722 / protein serine/threonine phosphatase activity => GO:0004722 / calcium-dependent protein serine/threonine phosphatase regulator activity / negative regulation of calcium ion import across plasma membrane / calmodulin-dependent protein phosphatase activity / calcineurin complex ...mitotic actomyosin contractile ring, intermediate layer / positive regulation of mitotic actomyosin contractile ring contraction / positive regulation of mitotic division septum assembly / fungal-type cell wall organization or biogenesis / protein serine/threonine phosphatase activity => GO:0004722 / protein serine/threonine phosphatase activity => GO:0004722 / calcium-dependent protein serine/threonine phosphatase regulator activity / negative regulation of calcium ion import across plasma membrane / calmodulin-dependent protein phosphatase activity / calcineurin complex / calcineurin-mediated signaling / protein-serine/threonine phosphatase / cellular response to calcium ion / ferric iron binding / peptidylprolyl isomerase / peptidyl-prolyl cis-trans isomerase activity / positive regulation of protein localization to nucleus / calmodulin binding / intracellular signal transduction / calcium ion binding / zinc ion binding / cytoplasm
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 / Chitinase A; domain 3 - #40 / Calcineurin-like phosphoesterase domain, ApaH type ...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 / Chitinase A; domain 3 - #40 / Calcineurin-like phosphoesterase domain, ApaH type / Calcineurin-like phosphoesterase / Metallo-dependent phosphatase-like / Chitinase A; domain 3 / FKBP-type peptidyl-prolyl cis-trans isomerase domain profile. / FKBP-type peptidyl-prolyl cis-trans isomerase domain / FKBP-type peptidyl-prolyl cis-trans isomerase / 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 / Roll / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
: / 8-DEETHYL-8-[BUT-3-ENYL]-ASCOMYCIN / Calcineurin regulatory subunit / Serine/threonine-protein phosphatase 2B catalytic subunit A1 / FK506-binding protein 1
Similarity search - Component
Biological speciesCryptococcus neoformans var. grubii serotype A (fungus)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.3 Å
AuthorsSeattle Structural Genomics Center for Infectious Disease (SSGCID)
Citation
Journal: Nat Commun / Year: 2019
Title: Harnessing calcineurin-FK506-FKBP12 crystal structures from invasive fungal pathogens to develop antifungal agents.
Authors: Juvvadi, P.R. / Fox 3rd, D. / Bobay, B.G. / Hoy, M.J. / Gobeil, S.M.C. / Venters, R.A. / Chang, Z. / Lin, J.J. / Averette, A.F. / Cole, D.C. / Barrington, B.C. / Wheaton, J.D. / Ciofani, M. ...Authors: Juvvadi, P.R. / Fox 3rd, D. / Bobay, B.G. / Hoy, M.J. / Gobeil, S.M.C. / Venters, R.A. / Chang, Z. / Lin, J.J. / Averette, A.F. / Cole, D.C. / Barrington, B.C. / Wheaton, J.D. / Ciofani, M. / Trzoss, M. / Li, X. / Lee, S.C. / Chen, Y.L. / Mutz, M. / Spicer, L.D. / Schumacher, M.A. / Heitman, J. / Steinbach, W.J.
#1: Journal: Nat Commun / Year: 2019
Title: Harnessing calcineurin-FK506-FKBP12 crystal structures from invasive fungal pathogens to develop antifungal agents
Authors: Juvvadi, P.R. / Fox III, D. / Bobay, B.G. / Hoy, M.J. / Gobeil, S.M. / Venters, R.A. / Chang, Z. / Lin, J.J. / Averette, A.F. / Cole, D.C. / Barrington, B.C. / Wheaton, J.D. / Ciofani, M. / ...Authors: Juvvadi, P.R. / Fox III, D. / Bobay, B.G. / Hoy, M.J. / Gobeil, S.M. / Venters, R.A. / Chang, Z. / Lin, J.J. / Averette, A.F. / Cole, D.C. / Barrington, B.C. / Wheaton, J.D. / Ciofani, M. / Trzoss, M. / Li, X. / Lee, S.C. / Chen, Y. / Mutz, M. / Spicer, L.D. / Schumacher, M.A. / Heitman, J. / Steinbach, W.J.
History
DepositionAug 10, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 18, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 2, 2019Group: Data collection / Database references / Category: citation / citation_author
Revision 1.2Oct 11, 2023Group: 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 ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _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

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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 A1
B: Calcineurin subunit B
C: FK506-binding protein 1
D: Serine/threonine-protein phosphatase 2B catalytic subunit A1
E: Calcineurin subunit B
F: FK506-binding protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)159,03323
Polymers156,5736
Non-polymers2,45917
Water1629
1
A: Serine/threonine-protein phosphatase 2B catalytic subunit A1
B: Calcineurin subunit B
C: FK506-binding protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)79,56412
Polymers78,2873
Non-polymers1,2789
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8810 Å2
ΔGint-199 kcal/mol
Surface area26860 Å2
MethodPISA
2
D: Serine/threonine-protein phosphatase 2B catalytic subunit A1
E: Calcineurin subunit B
F: FK506-binding protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)79,46811
Polymers78,2873
Non-polymers1,1828
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area8670 Å2
ΔGint-196 kcal/mol
Surface area27180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)118.720, 120.700, 134.960
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, 6 molecules ADBECF

#1: Protein Serine/threonine-protein phosphatase 2B catalytic subunit A1 / Calcineurin A1


Mass: 45253.305 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Cryptococcus neoformans var. grubii serotype A (strain H99 / ATCC 208821 / CBS 10515 / FGSC 9487) (fungus)
Strain: H99 / ATCC 208821 / CBS 10515 / FGSC 9487 / Gene: CNA1, CNAG_04796 / Plasmid: pEMB44 / Production host: Trichoplusia ni (cabbage looper) / Strain (production host): Tni
References: UniProt: O42773, protein-serine/threonine phosphatase
#2: Protein Calcineurin subunit B /


Mass: 19700.260 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Cryptococcus neoformans var. grubii serotype A (strain H99 / ATCC 208821 / CBS 10515 / FGSC 9487) (fungus)
Strain: H99 / ATCC 208821 / CBS 10515 / FGSC 9487 / Gene: CNAG_00888 / Plasmid: pEMB44 / Production host: Trichoplusia ni (cabbage looper) / Strain (production host): Tni / References: UniProt: J9VL81
#3: Protein FK506-binding protein 1 / FKBP / Peptidyl-prolyl cis-trans isomerase / PPIase / Rapamycin-binding protein


Mass: 13333.070 Da / Num. of mol.: 2 / Mutation: S9K, K14V
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Cryptococcus neoformans var. grubii serotype A (strain H99 / ATCC 208821 / CBS 10515 / FGSC 9487) (fungus)
Strain: H99 / ATCC 208821 / CBS 10515 / FGSC 9487 / Gene: FRR1, CNAG_03682 / Plasmid: pEMB44 / Production host: Trichoplusia ni (cabbage looper) / Strain (production host): Tni / References: UniProt: O94746, peptidylprolyl isomerase

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Non-polymers , 6 types, 26 molecules

#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-FE / FE (III) ION / Iron


Mass: 55.845 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Fe
#6: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#7: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Ca
#8: Chemical ChemComp-FK5 / 8-DEETHYL-8-[BUT-3-ENYL]-ASCOMYCIN / K506 / Tacrolimus


Mass: 804.018 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C44H69NO12 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication*YM
#9: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 9 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.24 Å3/Da / Density % sol: 62 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: CRYPTOCOCCUS NEOFORMANS CALCINEURIN A (CRNEC.00174.A.EX14), CALCINEURIN B (CRNEC.01011.A.FX11), AND FKBP12 (CRNEC.18272.A.DB13) WITH FK-506 IN 25MM MES PH6.4, 150MM NACL, 0.5MM TCEP, 5MM ...Details: CRYPTOCOCCUS NEOFORMANS CALCINEURIN A (CRNEC.00174.A.EX14), CALCINEURIN B (CRNEC.01011.A.FX11), AND FKBP12 (CRNEC.18272.A.DB13) WITH FK-506 IN 25MM MES PH6.4, 150MM NACL, 0.5MM TCEP, 5MM CACL2, 5UM FK506 WAS CRYSTALLIZED AT 9.38MG/ML AGAINST MORPHEUS II CONDITION A3 CONTAINING 30MM LITHIUM SULFATE, 30MM SODIUM SULFATE, 30MM POTASSIUM SULFATE, 0.1M MOPSO/0.1M BIS-TRIS PH6.5, 10% W/V PEG8000 AND 20% W/V 1, 5 PENTANEDIOL. CRYSTALS WERE DIRECTLY CRYO-PROTECTED IN 20% ETHYLENE GLYCOL
PH range: 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.9787 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Nov 9, 2016 / Details: BERYLLIUM LENSES
RadiationMonochromator: DIAMOND [111] / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9787 Å / Relative weight: 1
ReflectionResolution: 3.3→50 Å / Num. obs: 29795 / % possible obs: 99.9 % / Observed criterion σ(I): -3 / Redundancy: 6.2 % / CC1/2: 0.992 / Rmerge(I) obs: 0.196 / Rrim(I) all: 0.215 / Net I/σ(I): 8.62
Reflection shellResolution: 3.3→3.39 Å / Redundancy: 6.3 % / Rmerge(I) obs: 0.587 / Mean I/σ(I) obs: 3.3 / Num. unique obs: 2188 / CC1/2: 0.918 / Rrim(I) all: 0.642 / % possible all: 99.9

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
PHENIX(DEV_2919: ???)refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1TCO

1tco


Resolution: 3.3→44.57 Å / SU ML: 0.38 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 28.62
RfactorNum. reflection% reflection
Rfree0.2434 1479 4.98 %
Rwork0.1992 --
obs0.2013 29717 99.65 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 3.3→44.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms10119 0 141 9 10269
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00410510
X-RAY DIFFRACTIONf_angle_d0.65114299
X-RAY DIFFRACTIONf_dihedral_angle_d12.8546195
X-RAY DIFFRACTIONf_chiral_restr0.0421567
X-RAY DIFFRACTIONf_plane_restr0.0041874
LS refinement shell

Refine-ID: X-RAY DIFFRACTION

Resolution (Å)Highest resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
3.3-3.40650.31621332521100
3.4065-3.52820.33341362530100
3.5282-3.66940.32771322536100
3.6694-3.83630.31871322538100
3.8363-4.03840.24381302540100
4.0384-4.29130.21911290.17572560100
4.2913-4.62230.19621380.15992547100
4.6223-5.08690.18441340.16112561100
5.0869-5.82160.23271382579100
5.8216-7.32930.24511352622100
7.32930.18611420.1688270499

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