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- PDB-8xi9: Crystal structure of FRB-FKBP fusion protein in complex with rapamycin -

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Basic information

Entry
Database: PDB / ID: 8xi9
TitleCrystal structure of FRB-FKBP fusion protein in complex with rapamycin
ComponentsFRB-FKBP fusion protein
KeywordsSIGNALING PROTEIN / Rapamycin
Function / homology
Function and homology information


RNA polymerase III type 2 promoter sequence-specific DNA binding / RNA polymerase III type 1 promoter sequence-specific DNA binding / positive regulation of cytoplasmic translational initiation / regulation of locomotor rhythm / T-helper 1 cell lineage commitment / positive regulation of pentose-phosphate shunt / positive regulation of wound healing, spreading of epidermal cells / TORC2 complex / regulation of membrane permeability / TORC2 signaling ...RNA polymerase III type 2 promoter sequence-specific DNA binding / RNA polymerase III type 1 promoter sequence-specific DNA binding / positive regulation of cytoplasmic translational initiation / regulation of locomotor rhythm / T-helper 1 cell lineage commitment / positive regulation of pentose-phosphate shunt / positive regulation of wound healing, spreading of epidermal cells / TORC2 complex / regulation of membrane permeability / TORC2 signaling / cellular response to leucine starvation / macrolide binding / TFIIIC-class transcription factor complex binding / heart valve morphogenesis / negative regulation of lysosome organization / TORC1 complex / activin receptor binding / voluntary musculoskeletal movement / positive regulation of transcription of nucleolar large rRNA by RNA polymerase I / calcineurin-NFAT signaling cascade / RNA polymerase III type 3 promoter sequence-specific DNA binding / positive regulation of keratinocyte migration / regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion / regulation of osteoclast differentiation / cytoplasmic side of membrane / transforming growth factor beta receptor binding / MTOR signalling / TGFBR1 LBD Mutants in Cancer / regulation of lysosome organization / cellular response to L-leucine / energy reserve metabolic process / regulation of autophagosome assembly / type I transforming growth factor beta receptor binding / Energy dependent regulation of mTOR by LKB1-AMPK / cellular response to nutrient / signaling receptor inhibitor activity / Amino acids regulate mTORC1 / negative regulation of activin receptor signaling pathway / cellular response to methionine / serine/threonine protein kinase complex / ruffle organization / heart trabecula formation / negative regulation of cell size / positive regulation of ubiquitin-dependent protein catabolic process / I-SMAD binding / cellular response to osmotic stress / anoikis / inositol hexakisphosphate binding / negative regulation of protein localization to nucleus / regulation of amyloid precursor protein catabolic process / terminal cisterna / cardiac muscle cell development / ryanodine receptor complex / negative regulation of calcineurin-NFAT signaling cascade / regulation of myelination / positive regulation of transcription by RNA polymerase III / 'de novo' protein folding / negative regulation of macroautophagy / ventricular cardiac muscle tissue morphogenesis / TORC1 signaling / positive regulation of myotube differentiation / Macroautophagy / FK506 binding / regulation of cell size / Constitutive Signaling by AKT1 E17K in Cancer / positive regulation of actin filament polymerization / germ cell development / behavioral response to pain / TGF-beta receptor signaling activates SMADs / oligodendrocyte differentiation / positive regulation of oligodendrocyte differentiation / regulation of ryanodine-sensitive calcium-release channel activity / TOR signaling / positive regulation of translational initiation / mTORC1-mediated signalling / Calcineurin activates NFAT / CD28 dependent PI3K/Akt signaling / HSF1-dependent transactivation / regulation of macroautophagy / regulation of immune response / 'de novo' pyrimidine nucleobase biosynthetic process / response to amino acid / positive regulation of epithelial to mesenchymal transition / positive regulation of lipid biosynthetic process / vascular endothelial cell response to laminar fluid shear stress / heart morphogenesis / neuronal action potential / regulation of cellular response to heat / positive regulation of lamellipodium assembly / cardiac muscle contraction / positive regulation of stress fiber assembly / T cell costimulation / phagocytic vesicle / supramolecular fiber organization / cellular response to nutrient levels / cytoskeleton organization / endomembrane system / sarcoplasmic reticulum membrane / negative regulation of insulin receptor signaling pathway / negative regulation of autophagy
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 / Serine/threonine-protein kinase ATR-like, HEAT repeats / : ...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 / Serine/threonine-protein kinase ATR-like, HEAT repeats / : / FATC domain / PIK-related kinase, FAT / FAT domain / FATC / FATC domain / PIK-related kinase / FAT domain profile. / FATC domain profile. / : / Phosphatidylinositol 3- and 4-kinases signature 1. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3- and 4-kinases signature 2. / FKBP-type peptidyl-prolyl cis-trans isomerase / FKBP-type peptidyl-prolyl cis-trans isomerase domain / FKBP-type peptidyl-prolyl cis-trans isomerase domain profile. / 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
RAPAMYCIN IMMUNOSUPPRESSANT DRUG / 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
AuthorsInobe, T. / Sakaguchi, R. / Obita, T. / Mukaiyama, A. / Yokoyama, T. / Mizuguchi, M. / Akiyama, S.
Funding support Japan, 2items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)JP18H04544 Japan
Japan Society for the Promotion of Science (JSPS)JP19K06595 Japan
CitationJournal: Febs Lett. / Year: 2024
Title: Structural insights into rapamycin-induced oligomerization of a FRB-FKBP fusion protein.
Authors: Inobe, T. / Sakaguchi, R. / Obita, T. / Mukaiyama, A. / Koike, S. / Yokoyama, T. / Mizuguchi, M. / Akiyama, S.
History
DepositionDec 19, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 7, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 9, 2024Group: Database references / Structure summary / Category: citation / pdbx_entry_details
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: FRB-FKBP fusion protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,2452
Polymers23,3311
Non-polymers9141
Water2,072115
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: SAXS, forms a tetramer or pentamer structure
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)80.517, 80.517, 122.419
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number182
Space group name H-MP6322
Space group name HallP6c2c
Symmetry operation#1: x,y,z
#2: x-y,x,z+1/2
#3: y,-x+y,z+1/2
#4: -y,x-y,z
#5: -x+y,-x,z
#6: x-y,-y,-z
#7: -x,-x+y,-z
#8: -x,-y,z+1/2
#9: y,x,-z
#10: -y,-x,-z+1/2
#11: -x+y,y,-z+1/2
#12: x,x-y,-z+1/2
Components on special symmetry positions
IDModelComponents
11A-508-

HOH

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Components

#1: Protein FRB-FKBP fusion protein


Mass: 23330.688 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, FKBP1A, FKBP1, FKBP12
Production host: Escherichia coli (E. coli)
References: UniProt: P42345, UniProt: P62942, non-specific serine/threonine protein kinase, peptidylprolyl isomerase
#2: Chemical ChemComp-RAP / RAPAMYCIN IMMUNOSUPPRESSANT DRUG


Mass: 914.172 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C51H79NO13 / Feature type: SUBJECT OF INVESTIGATION / Comment: immunosuppressant, antibiotic*YM
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 115 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.45 Å3/Da / Density % sol: 49.9 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 7.4 / Details: 4.4M Sodium Acetate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Aug 27, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.85→69.73 Å / Num. obs: 20689 / % possible obs: 99.9 % / Redundancy: 37.3 % / Biso Wilson estimate: 25.31 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.059 / Rpim(I) all: 0.013 / Rrim(I) all: 0.06 / Net I/σ(I): 44.9
Reflection shellResolution: 1.85→1.89 Å / Rmerge(I) obs: 0.335 / Mean I/σ(I) obs: 13.2 / Num. unique obs: 1239 / CC1/2: 0.992 / Rpim(I) all: 0.075 / Rrim(I) all: 0.343

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
Cootmodel building
MOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.85→61.21 Å / SU ML: 0.1519 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 21.2749
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2184 1053 5.1 %
Rwork0.1872 19596 -
obs0.1887 20649 99.84 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 30.64 Å2
Refinement stepCycle: LAST / Resolution: 1.85→61.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1629 0 65 115 1809
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00721739
X-RAY DIFFRACTIONf_angle_d0.9492345
X-RAY DIFFRACTIONf_chiral_restr0.0513240
X-RAY DIFFRACTIONf_plane_restr0.0072303
X-RAY DIFFRACTIONf_dihedral_angle_d16.0185267
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.85-1.940.28311330.2112388X-RAY DIFFRACTION99.96
1.94-2.040.25521370.19362368X-RAY DIFFRACTION100
2.04-2.160.2131310.19372399X-RAY DIFFRACTION100
2.17-2.330.26281260.18822412X-RAY DIFFRACTION99.53
2.33-2.570.22331260.20552436X-RAY DIFFRACTION100
2.57-2.940.26861380.21622442X-RAY DIFFRACTION100
2.94-3.70.20541330.18792482X-RAY DIFFRACTION99.73
3.7-61.210.18021290.16472669X-RAY DIFFRACTION99.54
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.24773536942-0.9064490416180.5123126193875.14671920469-2.012872662913.16413346247-0.293735354967-0.687390928412-0.03451547455460.4930805248990.331238822979-0.109184205176-0.1059464232520.0180033883917-0.01670752922830.21177775960.0837337686556-0.02778599434550.3033156558220.01807350625950.1628769813114.692118682332.396869741725.1630003685
23.7295599921-0.3727894112970.154491877815.33181045488-0.5643161300522.63309890104-0.0476397055545-0.00693977164609-0.294468097959-0.04881571498430.1494480726620.5220727232650.0886375915504-0.201586035464-0.08323250828470.13861621070.0465923680183-0.01593857746490.1783966083710.04905485468040.1929304089069.7551444456730.449651005116.9102801935
33.32436918583-0.523024039613-1.00752551443.259201506531.096204811753.585461651170.1137439864950.2574307839240.0348123346235-0.1983339220210.1503313553610.1346890266470.0690816204765-0.395203642018-0.234698876250.144481992844-0.0226602600058-0.003635843296030.2721062486940.09009544165240.18705718347440.392627064641.0192309058.07585465379
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 2 through 44 )2 - 441 - 43
22chain 'A' and (resid 45 through 94 )45 - 9444 - 93
33chain 'A' and (resid 95 through 202 )95 - 20294 - 201

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