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- PDB-8ppz: Co-crystal structure of FKBP12, compound 7 and the FRB fragment o... -

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Basic information

Entry
Database: PDB / ID: 8ppz
TitleCo-crystal structure of FKBP12, compound 7 and the FRB fragment of mTOR
Components
  • Peptidyl-prolyl cis-trans isomerase FKBP1A
  • Serine/threonine-protein kinase mTOR
KeywordsISOMERASE / FKBP12 / mTOR / Kinase / Complex / molecular Glue
Function / homology
Function and homology information


positive regulation of cytoplasmic translational initiation / positive regulation of pentose-phosphate shunt / RNA polymerase III type 1 promoter sequence-specific DNA binding / RNA polymerase III type 2 promoter sequence-specific DNA binding / T-helper 1 cell lineage commitment / regulation of locomotor rhythm / positive regulation of wound healing, spreading of epidermal cells / cellular response to leucine starvation / regulation of membrane permeability / TFIIIC-class transcription factor complex binding ...positive regulation of cytoplasmic translational initiation / positive regulation of pentose-phosphate shunt / RNA polymerase III type 1 promoter sequence-specific DNA binding / RNA polymerase III type 2 promoter sequence-specific DNA binding / T-helper 1 cell lineage commitment / regulation of locomotor rhythm / positive regulation of wound healing, spreading of epidermal cells / cellular response to leucine starvation / regulation of membrane permeability / TFIIIC-class transcription factor complex binding / heart valve morphogenesis / negative regulation of lysosome organization / macrolide binding / RNA polymerase III type 3 promoter sequence-specific DNA binding / TORC2 complex / activin receptor binding / TORC1 complex / positive regulation of transcription of nucleolar large rRNA by RNA polymerase I / cytoplasmic side of membrane / regulation of autophagosome assembly / calcineurin-NFAT signaling cascade / nucleus localization / TORC1 signaling / voluntary musculoskeletal movement / regulation of osteoclast differentiation / positive regulation of keratinocyte migration / signaling receptor inhibitor activity / transforming growth factor beta receptor binding / TGFBR1 LBD Mutants in Cancer / cellular response to L-leucine / MTOR signalling / Amino acids regulate mTORC1 / cellular response to nutrient / energy reserve metabolic process / type I transforming growth factor beta receptor binding / Energy dependent regulation of mTOR by LKB1-AMPK / negative regulation of activin receptor signaling pathway / negative regulation of cell size / heart trabecula formation / ruffle organization / cellular response to osmotic stress / terminal cisterna / ryanodine receptor complex / I-SMAD binding / negative regulation of protein localization to nucleus / anoikis / regulation of amyloid precursor protein catabolic process / cardiac muscle cell development / positive regulation of transcription by RNA polymerase III / protein maturation by protein folding / negative regulation of calcineurin-NFAT signaling cascade / ventricular cardiac muscle tissue morphogenesis / 'de novo' protein folding / regulation of myelination / regulation of cell size / Macroautophagy / negative regulation of phosphoprotein phosphatase activity / positive regulation of oligodendrocyte differentiation / negative regulation of macroautophagy / FK506 binding / positive regulation of actin filament polymerization / lysosome organization / positive regulation of myotube differentiation / behavioral response to pain / oligodendrocyte differentiation / Constitutive Signaling by AKT1 E17K in Cancer / mTORC1-mediated signalling / TGF-beta receptor signaling activates SMADs / germ cell development / CD28 dependent PI3K/Akt signaling / cellular response to nutrient levels / positive regulation of phosphoprotein phosphatase activity / Calcineurin activates NFAT / HSF1-dependent transactivation / regulation of immune response / TOR signaling / neuronal action potential / positive regulation of translational initiation / response to amino acid / regulation of macroautophagy / endomembrane system / 'de novo' pyrimidine nucleobase biosynthetic process / protein peptidyl-prolyl isomerization / positive regulation of lamellipodium assembly / positive regulation of epithelial to mesenchymal transition / positive regulation of lipid biosynthetic process / heart morphogenesis / cardiac muscle contraction / supramolecular fiber organization / regulation of cellular response to heat / regulation of ryanodine-sensitive calcium-release channel activity / positive regulation of stress fiber assembly / cytoskeleton organization / sarcoplasmic reticulum membrane / T cell costimulation / T cell activation / cellular response to amino acid starvation / phagocytic vesicle / positive regulation of glycolytic process / cellular response to starvation
Similarity search - Function
Domain of unknown function DUF3385, target of rapamycin protein / Serine/threonine-protein kinase mTOR domain / Domain of unknown function / FKBP12-rapamycin binding domain / Serine/threonine-protein kinase TOR / FKBP12-rapamycin binding domain superfamily / FKBP12-rapamycin binding domain / Rapamycin binding domain / PIK-related kinase, FAT / FAT domain ...Domain of unknown function DUF3385, target of rapamycin protein / Serine/threonine-protein kinase mTOR domain / Domain of unknown function / FKBP12-rapamycin binding domain / Serine/threonine-protein kinase TOR / FKBP12-rapamycin binding domain superfamily / FKBP12-rapamycin binding domain / Rapamycin binding domain / PIK-related kinase, FAT / FAT domain / FATC domain / FATC / FATC domain / PIK-related kinase / FAT domain profile. / FATC domain profile. / FKBP-type peptidyl-prolyl cis-trans isomerase domain profile. / FKBP-type peptidyl-prolyl cis-trans isomerase domain / FKBP-type peptidyl-prolyl cis-trans isomerase / Phosphatidylinositol 3- and 4-kinases signature 1. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3- and 4-kinases signature 2. / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / Peptidyl-prolyl cis-trans isomerase domain superfamily / Armadillo-like helical / Tetratricopeptide-like helical domain superfamily / Armadillo-type fold / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-0AN / ACETATE ION / Serine/threonine-protein kinase mTOR / Peptidyl-prolyl cis-trans isomerase FKBP1A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsMeyners, C. / Deutscher, R.C.E. / Hausch, F.
Funding support Germany, 2items
OrganizationGrant numberCountry
German Federal Ministry for Education and Research03ZU1109EB Germany
German Research Foundation (DFG)HA5556 Germany
CitationJournal: Chemrxiv / Year: 2023
Title: Co-crystal structure of FKBP12, compound 7 and the FRB fragment of mTOR
Authors: Meyners, C. / Deutscher, R.C.E. / Hausch, F.
History
DepositionJul 10, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 9, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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: Serine/threonine-protein kinase mTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,3908
Polymers23,5802
Non-polymers8106
Water2,306128
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1620 Å2
ΔGint-41 kcal/mol
Surface area10480 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.912, 64.680, 93.349
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP22121
Components on special symmetry positions
IDModelComponents
11B-2202-

CA

21B-2326-

HOH

31B-2331-

HOH

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Components

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Protein , 2 types, 2 molecules AB

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


Mass: 11832.496 Da / Num. of mol.: 1 / Mutation: C22V
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FKBP1A, FKBP1, FKBP12
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P62942, peptidylprolyl isomerase
#2: Protein Serine/threonine-protein kinase mTOR / FK506-binding protein 12-rapamycin complex-associated protein 1 / FKBP12-rapamycin complex- ...FK506-binding protein 12-rapamycin complex-associated protein 1 / FKBP12-rapamycin complex-associated protein / Mammalian target of rapamycin / mTOR / Mechanistic target of rapamycin / Rapamycin and FKBP12 target 1 / Rapamycin target protein 1


Mass: 11747.374 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MTOR, FRAP, FRAP1, FRAP2, RAFT1, RAPT1
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P42345, non-specific serine/threonine protein kinase

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Non-polymers , 4 types, 134 molecules

#3: Chemical ChemComp-0AN / (1~{S},5~{S},6~{R})-10-[3,5-bis(chloranyl)phenyl]sulfonyl-5-[(~{E})-2-(2-chlorophenyl)ethenyl]-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one


Mass: 590.948 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H26Cl3N3O3S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ca
#5: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 128 / 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: 2.55 Å3/Da / Density % sol: 51.86 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 10% PEG8000, 0.1 M HEPES pH 7.5, 0.2 M calcium actetate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P13 (MX1) / Wavelength: 0.97626 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Nov 26, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97626 Å / Relative weight: 1
ReflectionResolution: 1.85→93.35 Å / Num. obs: 20522 / % possible obs: 96 % / Redundancy: 12.8 % / CC1/2: 0.999 / Rmerge(I) obs: 0.106 / Rpim(I) all: 0.044 / Rrim(I) all: 0.115 / Net I/σ(I): 15.2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all
9.06-93.3510.60.0482370.9990.0190.052
1.85-1.8912.41.36712790.8060.5791.487

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Processing

Software
NameVersionClassification
REFMAC5.8.0415refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.85→46.718 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.936 / SU B: 3.573 / SU ML: 0.101 / Cross valid method: THROUGHOUT / ESU R: 0.138 / ESU R Free: 0.137
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2383 1055 5.151 %
Rwork0.192 19425 -
all0.194 --
obs-20480 96.042 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 29.647 Å2
Baniso -1Baniso -2Baniso -3
1-2.918 Å20 Å2-0 Å2
2---2.693 Å20 Å2
3----0.225 Å2
Refinement stepCycle: LAST / Resolution: 1.85→46.718 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1590 0 46 128 1764
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0121675
X-RAY DIFFRACTIONr_bond_other_d0.0030.0161521
X-RAY DIFFRACTIONr_angle_refined_deg1.6611.7012263
X-RAY DIFFRACTIONr_angle_other_deg0.6381.6123503
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2035199
X-RAY DIFFRACTIONr_dihedral_angle_2_deg6.609511
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.9710275
X-RAY DIFFRACTIONr_dihedral_angle_6_deg15.9161078
X-RAY DIFFRACTIONr_chiral_restr0.1740.2230
X-RAY DIFFRACTIONr_chiral_restr_other1.4830.25
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.021980
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02399
X-RAY DIFFRACTIONr_nbd_refined0.2180.2333
X-RAY DIFFRACTIONr_symmetry_nbd_other0.190.21329
X-RAY DIFFRACTIONr_nbtor_refined0.1840.2830
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.080.2859
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1680.2113
X-RAY DIFFRACTIONr_metal_ion_refined0.0840.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1880.212
X-RAY DIFFRACTIONr_nbd_other0.1120.241
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1750.225
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined0.110.22
X-RAY DIFFRACTIONr_mcbond_it2.8453.113806
X-RAY DIFFRACTIONr_mcbond_other2.8213.11805
X-RAY DIFFRACTIONr_mcangle_it3.8635.5811001
X-RAY DIFFRACTIONr_mcangle_other3.8615.5841002
X-RAY DIFFRACTIONr_scbond_it3.9373.356869
X-RAY DIFFRACTIONr_scbond_other3.9353.357870
X-RAY DIFFRACTIONr_scangle_it5.73361262
X-RAY DIFFRACTIONr_scangle_other5.736.0011263
X-RAY DIFFRACTIONr_lrange_it7.46330.8811959
X-RAY DIFFRACTIONr_lrange_other7.34230.271924
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
1.85-1.8980.32810.29414790.29615600.9210.9061000.278
1.898-1.950.3480.3139410.31214870.9140.88766.50980.283
1.95-2.0060.307610.26412470.26614720.9240.94588.85870.239
2.006-2.0680.29900.22813290.23214190.940.9591000.202
2.068-2.1360.263760.22712930.22913690.9450.9621000.198
2.136-2.210.246630.20112800.20313430.9620.971000.176
2.21-2.2940.253570.19510630.19812950.9540.97286.48650.164
2.294-2.3870.22750.18111920.18312670.9720.9781000.157
2.387-2.4930.236620.17411410.17812030.9710.9811000.155
2.493-2.6140.217480.16911130.17111610.9760.9831000.148
2.614-2.7550.206600.16910270.1710870.9770.9821000.15
2.755-2.9220.293530.2029990.20610520.940.9731000.186
2.922-3.1230.237580.2029190.2049770.960.9741000.188
3.123-3.3710.204520.1868670.1879190.9780.9781000.178
3.371-3.6910.186340.28160.1998500.9760.9781000.194
3.691-4.1240.242370.1737450.1757870.9710.98399.36470.176
4.124-4.7560.253240.1426690.1456930.9650.9881000.151
4.756-5.8090.203320.1725700.1746030.9740.98599.83420.178
5.809-8.1530.24260.1924580.1944840.9630.981000.196
8.153-46.7180.256180.2052780.2082960.9730.9671000.215

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