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- PDB-4dri: Co-crystal structure of the PPIase domain of FKBP51, Rapamycin an... -

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Basic information

Entry
Database: PDB / ID: 4dri
TitleCo-crystal structure of the PPIase domain of FKBP51, Rapamycin and the FRB fragment of mTOR
Components
  • Peptidyl-prolyl cis-trans isomerase FKBP5
  • Serine/threonine-protein kinase mTOR
KeywordsIsomerase/Transferase / Fk-506 binding domain / Hsp90 cochaperone / immunophilin / peptidyl-prolyl isomerase / mammalian target of Rapamycin / kinase / signalling / immunosuppression / cancer / Isomerase-Transferase complex
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 signaling / TORC2 complex / regulation of membrane permeability ...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 signaling / TORC2 complex / regulation of membrane permeability / cellular response to leucine starvation / negative regulation of lysosome organization / heart valve morphogenesis / TFIIIC-class transcription factor complex binding / TORC1 complex / 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 osteoclast differentiation / regulation of lysosome organization / MTOR signalling / cellular response to nutrient / cellular response to L-leucine / Amino acids regulate mTORC1 / energy reserve metabolic process / regulation of autophagosome assembly / Energy dependent regulation of mTOR by LKB1-AMPK / TORC1 signaling / ruffle organization / serine/threonine protein kinase complex / cellular response to methionine / negative regulation of cell size / positive regulation of ubiquitin-dependent protein catabolic process / cellular response to osmotic stress / negative regulation of protein localization to nucleus / anoikis / inositol hexakisphosphate binding / Modulation of host responses by IFN-stimulated genes / cardiac muscle cell development / response to alcohol / negative regulation of calcineurin-NFAT signaling cascade / regulation of myelination / positive regulation of transcription by RNA polymerase III / negative regulation of macroautophagy / Macroautophagy / positive regulation of myotube differentiation / FK506 binding / regulation of cell size / Constitutive Signaling by AKT1 E17K in Cancer / positive regulation of actin filament polymerization / germ cell development / TOR signaling / behavioral response to pain / mTORC1-mediated signalling / oligodendrocyte differentiation / positive regulation of oligodendrocyte differentiation / positive regulation of translational initiation / CD28 dependent PI3K/Akt signaling / HSF1-dependent transactivation / regulation of macroautophagy / response to amino acid / 'de novo' pyrimidine nucleobase biosynthetic process / positive regulation of epithelial to mesenchymal transition / vascular endothelial cell response to laminar fluid shear stress / positive regulation of lipid biosynthetic process / heart morphogenesis / cellular response to nutrient levels / neuronal action potential / regulation of cellular response to heat / MECP2 regulates neuronal receptors and channels / positive regulation of lamellipodium assembly / cardiac muscle contraction / phagocytic vesicle / T cell costimulation / positive regulation of stress fiber assembly / : / heat shock protein binding / cytoskeleton organization / endomembrane system / negative regulation of insulin receptor signaling pathway / negative regulation of autophagy / cellular response to amino acid starvation / ESR-mediated signaling / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / positive regulation of translation / regulation of signal transduction by p53 class mediator / positive regulation of glycolytic process / cellular response to starvation / Regulation of PTEN gene transcription / VEGFR2 mediated vascular permeability / post-embryonic development / response to cocaine / TP53 Regulates Metabolic Genes / regulation of actin cytoskeleton organization / response to bacterium / peptidylprolyl isomerase / cellular response to amino acid stimulus / non-specific protein-tyrosine kinase
Similarity search - Function
FKBP12-rapamycin binding 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 / Serine/threonine-protein kinase ATR-like, HEAT repeats ...FKBP12-rapamycin binding 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 / Serine/threonine-protein kinase ATR-like, HEAT repeats / : / : / FATC domain / Chitinase A; domain 3 - #40 / PIK-related kinase, FAT / FAT domain / FATC / FATC domain / PIK-related kinase / FAT domain profile. / FATC domain profile. / Tetratricopeptide repeat / Chitinase A; domain 3 / Tetratricopeptide repeat / 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 / TPR repeat region circular profile. / Peptidyl-prolyl cis-trans isomerase domain superfamily / TPR repeat profile. / Tetratricopeptide repeats / Tetratricopeptide repeat / Four Helix Bundle (Hemerythrin (Met), subunit A) / Armadillo-like helical / Tetratricopeptide-like helical domain superfamily / Armadillo-type fold / Roll / Protein kinase-like domain superfamily / Up-down Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
RAPAMYCIN IMMUNOSUPPRESSANT DRUG / Serine/threonine-protein kinase mTOR / Peptidyl-prolyl cis-trans isomerase FKBP5
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.45 Å
AuthorsMaerz, A.M. / Bracher, A. / Hausch, F.
CitationJournal: Mol.Cell.Biol. / Year: 2013
Title: Large FK506-Binding Proteins Shape the Pharmacology of Rapamycin.
Authors: Marz, A.M. / Fabian, A.K. / Kozany, C. / Bracher, A. / Hausch, F.
History
DepositionFeb 17, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 6, 2013Provider: repository / Type: Initial release
Revision 1.1Mar 27, 2013Group: Database references
Revision 1.2Sep 13, 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_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Peptidyl-prolyl cis-trans isomerase FKBP5
B: Serine/threonine-protein kinase mTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,3553
Polymers27,4412
Non-polymers9141
Water4,017223
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)59.503, 59.554, 67.787
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Peptidyl-prolyl cis-trans isomerase FKBP5 / PPIase FKBP5 / 51 kDa FK506-binding protein / 51 kDa FKBP / FKBP-51 / 54 kDa progesterone receptor- ...PPIase FKBP5 / 51 kDa FK506-binding protein / 51 kDa FKBP / FKBP-51 / 54 kDa progesterone receptor-associated immunophilin / Androgen-regulated protein 6 / FF1 antigen / FK506-binding protein 5 / FKBP-5 / FKBP54 / p54 / HSP90-binding immunophilin / Rotamase


Mass: 15693.832 Da / Num. of mol.: 1 / Fragment: FKBP51 Fk1 domain, UNP residues 1-140
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AIG6, FKBP5, FKBP51 / Plasmid: pProEx-Hta / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q13451, 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 / Fragment: FRB domain, UNP residues 2025-2114
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FRAP, FRAP1, FRAP2, MTOR, RAFT1, RAPT1 / Plasmid: pProEx-Hta / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: P42345, non-specific serine/threonine protein kinase
#3: Chemical ChemComp-RAP / RAPAMYCIN IMMUNOSUPPRESSANT DRUG


Mass: 914.172 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C51H79NO13 / Comment: antibiotic*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 223 / Source method: isolated from a natural source / Formula: H2O

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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: 2.21 Å3/Da / Density % sol: 44.44 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 7.5
Details: 25% PEG3350, 0.1 M NaCl, 0.1M HEPES-NaOH pH 7.5, vapor diffusion, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.9788 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Sep 25, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9788 Å / Relative weight: 1
ReflectionResolution: 1.45→67.787 Å / Num. all: 41315 / Num. obs: 41315 / % possible obs: 95.7 % / Redundancy: 3.8 % / Biso Wilson estimate: 18.77 Å2 / Rmerge(I) obs: 0.043 / Rsym value: 0.043 / Net I/σ(I): 17.3
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
1.45-1.533.50.37722044558060.37793.8
1.53-1.623.60.2063.71987955540.20694.7
1.62-1.733.60.1315.81917352850.13195.1
1.73-1.873.70.0759.61818549700.07595.8
1.87-2.053.60.04714.81669845780.04795.7
2.05-2.293.60.03617.51507941780.03696.2
2.29-2.653.50.03317.31324637390.03397.3
2.65-3.244.50.04113.11444932120.04197.3
3.24-4.595.60.04213.41399025170.04297.6
4.59-67.7874.90.0318.2719814760.0397.7

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation3 Å67.79 Å
Translation3 Å67.79 Å

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Processing

Software
NameVersionClassificationNB
MOSFLMdata reduction
SCALA3.3.1data scaling
MOLREPphasing
REFMACrefinement
PDB_EXTRACT3.1data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1FAP

1fap


Resolution: 1.45→19.05 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.956 / WRfactor Rfree: 0.2746 / WRfactor Rwork: 0.2452 / Occupancy max: 1 / Occupancy min: 0.3 / FOM work R set: 0.879 / SU B: 2.294 / SU ML: 0.044 / SU R Cruickshank DPI: 0.0863 / SU Rfree: 0.0856 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.069 / ESU R Free: 0.071 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2064 2062 5 %RANDOM
Rwork0.1769 ---
all0.1784 41275 --
obs0.1784 39213 95.16 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 80.84 Å2 / Biso mean: 25.4582 Å2 / Biso min: 10.28 Å2
Baniso -1Baniso -2Baniso -3
1--0.04 Å20 Å20 Å2
2---0.04 Å20 Å2
3---0.08 Å2
Refinement stepCycle: LAST / Resolution: 1.45→19.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1718 0 65 223 2006
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0221911
X-RAY DIFFRACTIONr_angle_refined_deg1.5462.0012580
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7785233
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.61824.3982
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.00915345
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.59158
X-RAY DIFFRACTIONr_chiral_restr0.10.2266
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.021451
X-RAY DIFFRACTIONr_nbd_refined0.2090.2859
X-RAY DIFFRACTIONr_nbtor_refined0.3120.21355
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1290.2177
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2030.250
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0820.211
X-RAY DIFFRACTIONr_mcbond_it0.9541.51152
X-RAY DIFFRACTIONr_mcangle_it1.43521803
X-RAY DIFFRACTIONr_scbond_it2.2813854
X-RAY DIFFRACTIONr_scangle_it3.4714.5777
LS refinement shellResolution: 1.45→1.488 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.257 151 -
Rwork0.24 2695 -
all-2846 -
obs--91.81 %
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)
15.7827-2.5658-5.13485.052.24147.7960.02750.29020.2152-0.18830.07960.1687-0.2522-0.3925-0.1072-0.0860.0274-0.0211-0.0760.051-0.135534.845565.933521.2544
25.20361.83822.12053.72621.18023.6289-0.12680.2177-0.0691-0.03860.1042-0.1204-0.05050.09320.0226-0.13490.01140.0339-0.12390.0064-0.156939.071354.854926.2497
31.87860.5031-0.15352.5668-0.03443.072-0.06520.0486-0.1094-0.06980.0918-0.02740.0397-0.0953-0.0266-0.15070.0084-0.0032-0.1111-0.0081-0.14935.480555.284627.2464
41.61120.42430.92352.73792.04596.38530.0508-0.0984-0.06660.1874-0.0641-0.06740.1763-0.36250.0133-0.1310.0194-0.0109-0.1066-0.0013-0.131338.079156.667832.2343
54.89782.47752.11889.34651.43783.6990.1940.193-0.6070.0571-0.02340.75840.4538-0.524-0.1706-0.0541-0.0631-0.02160.02890.02460.162227.185732.35740.4655
63.9168-0.29390.31477.5080.12193.7775-0.0342-0.4333-0.15510.8580.14860.4226-0.1281-0.2725-0.1145-0.0450.02670.04540.00060.0366-0.037733.373142.423547.9172
710.91523.5423-2.064811.86764.7966.11-0.24510.0983-1.20290.4997-0.06060.18420.9537-0.36870.30570.1602-0.0153-0.0172-0.1025-0.10250.330835.923423.202638.7242
86.16220.63123.6634.14841.0836.4611-0.0081-0.0396-0.17940.02920.018-0.06770.109-0.0461-0.0098-0.12670.0165-0.009-0.1462-0.0067-0.069642.953939.621742.3499
91.6587-1.178-0.95465.9961-1.27145.01550.0162-0.2242-0.17320.11520.02350.07420.119-0.0359-0.0397-0.12610.0190.0032-0.10510.0079-0.128235.515649.948536.0279
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A20 - 43
2X-RAY DIFFRACTION2A44 - 69
3X-RAY DIFFRACTION3A70 - 114
4X-RAY DIFFRACTION4A115 - 140
5X-RAY DIFFRACTION5B2017 - 2034
6X-RAY DIFFRACTION6B2035 - 2056
7X-RAY DIFFRACTION7B2057 - 2074
8X-RAY DIFFRACTION8B2075 - 2112
9X-RAY DIFFRACTION9A201

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