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- PDB-6vcu: Homo sapiens FKBP12 protein bound with APX879 in P32 space group -

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Basic information

Entry
Database: PDB / ID: 6vcu
TitleHomo sapiens FKBP12 protein bound with APX879 in P32 space group
ComponentsPeptidyl-prolyl cis-trans isomerase FKBP1A
KeywordsISOMERASE / FK506-binding protein 1A / FKBP12 / FK506
Function / homology
Function and homology information


macrolide binding / activin receptor binding / cytoplasmic side of membrane / transforming growth factor beta receptor binding / TGFBR1 LBD Mutants in Cancer / signaling receptor inhibitor activity / type I transforming growth factor beta receptor binding / negative regulation of activin receptor signaling pathway / regulation of amyloid precursor protein catabolic process / heart trabecula formation ...macrolide binding / activin receptor binding / cytoplasmic side of membrane / transforming growth factor beta receptor binding / TGFBR1 LBD Mutants in Cancer / signaling receptor inhibitor activity / type I transforming growth factor beta receptor binding / negative regulation of activin receptor signaling pathway / regulation of amyloid precursor protein catabolic process / heart trabecula formation / terminal cisterna / ryanodine receptor complex / I-SMAD binding / protein maturation by protein folding / 'de novo' protein folding / ventricular cardiac muscle tissue morphogenesis / negative regulation of phosphoprotein phosphatase activity / FK506 binding / mTORC1-mediated signalling / TGF-beta receptor signaling activates SMADs / Calcineurin activates NFAT / regulation of immune response / protein peptidyl-prolyl isomerization / supramolecular fiber organization / heart morphogenesis / regulation of ryanodine-sensitive calcium-release channel activity / sarcoplasmic reticulum membrane / T cell activation / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / sarcoplasmic reticulum / peptidylprolyl isomerase / peptidyl-prolyl cis-trans isomerase activity / calcium ion transmembrane transport / negative regulation of transforming growth factor beta receptor signaling pathway / Z disc / SARS-CoV-1 activates/modulates innate immune responses / regulation of protein localization / protein folding / positive regulation of protein binding / protein refolding / positive regulation of canonical NF-kappaB signal transduction / amyloid fibril formation / Potential therapeutics for SARS / transmembrane transporter binding / membrane / cytosol / cytoplasm
Similarity search - Function
FKBP-type peptidyl-prolyl cis-trans isomerase domain profile. / FKBP-type peptidyl-prolyl cis-trans isomerase domain / FKBP-type peptidyl-prolyl cis-trans isomerase / Peptidyl-prolyl cis-trans isomerase domain superfamily
Similarity search - Domain/homology
ACETATE ION / Chem-R27 / Peptidyl-prolyl cis-trans isomerase FKBP1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.69 Å
AuthorsGobeil, S. / Spicer, L.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01-AI112595 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)P01-AI104533 United States
Citation
Journal: Mbio / Year: 2021
Title: Leveraging Fungal and Human Calcineurin-Inhibitor Structures, Biophysical Data, and Dynamics To Design Selective and Nonimmunosuppressive FK506 Analogs.
Authors: Gobeil, S.M. / Bobay, B.G. / Juvvadi, P.R. / Cole, D.C. / Heitman, J. / Steinbach, W.J. / Venters, R.A. / Spicer, L.D.
#1: Journal: Biorxiv / Year: 2020
Title: Designing Selective and Non-Immunosuppressive Antifungal FK506 Analogs: Structures, Biophysics and Dynamics of Fungal and Human Calcineurin-Inhibitor Complexes
Authors: Gobeil, S.M. / Bobay, B.G. / Juvvadi, P.R. / Cole, D.C. / Heitman, J. / Steinbach, W.J. / Venters, R.A. / Spicer, L.D.
History
DepositionDec 23, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 16, 2020Provider: repository / Type: Initial release
Revision 1.1Aug 9, 2023Group: Database references / Category: citation / citation_author / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Oct 11, 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 FKBP1A
B: Peptidyl-prolyl cis-trans isomerase FKBP1A
C: Peptidyl-prolyl cis-trans isomerase FKBP1A
D: Peptidyl-prolyl cis-trans isomerase FKBP1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,73513
Polymers49,0004
Non-polymers3,7369
Water10,647591
1
A: Peptidyl-prolyl cis-trans isomerase FKBP1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,2284
Polymers12,2501
Non-polymers9783
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Peptidyl-prolyl cis-trans isomerase FKBP1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,2284
Polymers12,2501
Non-polymers9783
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Peptidyl-prolyl cis-trans isomerase FKBP1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,1102
Polymers12,2501
Non-polymers8601
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Peptidyl-prolyl cis-trans isomerase FKBP1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,1693
Polymers12,2501
Non-polymers9192
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)53.593, 53.593, 126.891
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number145
Space group name H-MP32
Space group name HallP32
Symmetry operation#1: x,y,z
#2: -y,x-y,z+2/3
#3: -x+y,-x,z+1/3

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Components

#1: Protein
Peptidyl-prolyl cis-trans isomerase FKBP1A / PPIase FKBP1A / 12 kDa FK506-binding protein / FKBP-12 / Calstabin-1 / FK506-binding protein 1A / ...PPIase FKBP1A / 12 kDa FK506-binding protein / FKBP-12 / Calstabin-1 / FK506-binding protein 1A / FKBP-1A / Immunophilin FKBP12 / Rotamase


Mass: 12249.980 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FKBP1A, FKBP1, FKBP12 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P62942, peptidylprolyl isomerase
#2: Chemical
ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H3O2
#3: Chemical
ChemComp-R27 / N'-[(3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,19R,26aS)-5,19-dihydroxy-3-{(1E)-1-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]prop-1-en-2-yl}-14,16-dimethoxy-4,10,12,18-tetramethyl-1,20,21-trioxo-8-(prop-2-en-1-yl)-1,3,4,5,6,8,11,12,13,14,15,16,17,18,19,20,21,23,24,25,26,26a-docosahydro-7H-15,19-epoxypyrido[2,1-c][1,4]oxazacyclotricosin-7-ylidene]acetohydrazide / APX879


Mass: 860.085 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: C46H73N3O12 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 591 / 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: 2.2 Å3/Da / Density % sol: 44.03 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 4.6
Details: 2.5M Ammonium sulfate, 0.1M Sodium acetate trihydrate

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1 Å
DetectorType: RAYONIX MX300-HS / Detector: CCD / Date: Apr 21, 2019
RadiationMonochromator: 1 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.69→50 Å / Num. obs: 45479 / % possible obs: 100 % / Redundancy: 6.5 % / Biso Wilson estimate: 12.72 Å2 / CC1/2: 0.985 / Rpim(I) all: 0.053 / Rrim(I) all: 0.135 / Rsym value: 0.125 / Net I/σ(I): 30.5
Reflection shellResolution: 1.69→1.72 Å / Redundancy: 6.2 % / Mean I/σ(I) obs: 5.7 / Num. unique obs: 2284 / CC1/2: 0.94 / Rpim(I) all: 0.139 / Rrim(I) all: 0.349 / Rsym value: 0.32 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2PPN

2ppn


Resolution: 1.69→31.26 Å / SU ML: 0.1555 / Cross valid method: FREE R-VALUE / σ(F): 2.05 / Phase error: 18.2937
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1955 2006 4.42 %
Rwork0.1559 43416 -
obs0.1576 45422 99.94 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 15.68 Å2
Refinement stepCycle: LAST / Resolution: 1.69→31.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3344 0 264 591 4199
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0073736
X-RAY DIFFRACTIONf_angle_d1.19095062
X-RAY DIFFRACTIONf_chiral_restr0.0572555
X-RAY DIFFRACTIONf_plane_restr0.006651
X-RAY DIFFRACTIONf_dihedral_angle_d27.7557533
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.69-1.730.21361380.17173113X-RAY DIFFRACTION99.45
1.73-1.780.19721460.16293109X-RAY DIFFRACTION100
1.78-1.830.18881440.1573070X-RAY DIFFRACTION100
1.83-1.890.22961360.15493132X-RAY DIFFRACTION100
1.89-1.960.19641500.14363081X-RAY DIFFRACTION100
1.96-2.040.21371460.15523078X-RAY DIFFRACTION100
2.04-2.130.18851400.15033133X-RAY DIFFRACTION100
2.13-2.240.21511410.15643122X-RAY DIFFRACTION100
2.24-2.380.25161420.16013076X-RAY DIFFRACTION100
2.39-2.570.191480.16643125X-RAY DIFFRACTION100
2.57-2.830.21841480.16723098X-RAY DIFFRACTION99.97
2.83-3.240.19521520.16483052X-RAY DIFFRACTION100
3.24-4.080.17421440.13363114X-RAY DIFFRACTION100
4.08-31.260.1611310.15983113X-RAY DIFFRACTION99.78

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