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- PDB-4drj: o-crystal structure of the PPIase domain of FKBP52, Rapamycin and... -

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Basic information

Entry
Database: PDB / ID: 4drj
Titleo-crystal structure of the PPIase domain of FKBP52, Rapamycin and the FRB fragment of mTOR
Components
  • Peptidyl-prolyl cis-trans isomerase FKBP4
  • Serine/threonine-protein kinase mTOR
KeywordsIsomerase/Transferase / Fk-506 binding domain / Hsp90 cochaperone / immunophilin / peptidyl-prolyl isomerase / kinase / signalling / mammalian target of Rapamycin / immunosuppression / cancer / Isomerase-Transferase complex
Function / homology
Function and homology information


steroid hormone receptor complex assembly / negative regulation of microtubule polymerization or depolymerization / male sex differentiation / copper-dependent protein binding / RNA polymerase III type 2 promoter sequence-specific DNA binding / positive regulation of cytoplasmic translational initiation / RNA polymerase III type 1 promoter sequence-specific DNA binding / positive regulation of pentose-phosphate shunt / T-helper 1 cell lineage commitment / regulation of locomotor rhythm ...steroid hormone receptor complex assembly / negative regulation of microtubule polymerization or depolymerization / male sex differentiation / copper-dependent protein binding / RNA polymerase III type 2 promoter sequence-specific DNA binding / positive regulation of cytoplasmic translational initiation / RNA polymerase III type 1 promoter sequence-specific DNA binding / positive regulation of pentose-phosphate shunt / T-helper 1 cell lineage commitment / regulation of locomotor rhythm / positive regulation of wound healing, spreading of epidermal cells / cellular response to leucine starvation / TFIIIC-class transcription factor complex binding / TORC2 complex / regulation of membrane permeability / heart valve morphogenesis / negative regulation of lysosome organization / prostate gland development / RNA polymerase III type 3 promoter sequence-specific DNA binding / TORC1 complex / positive regulation of transcription of nucleolar large rRNA by RNA polymerase I / calcineurin-NFAT signaling cascade / regulation of autophagosome assembly / TORC1 signaling / voluntary musculoskeletal movement / regulation of osteoclast differentiation / nuclear glucocorticoid receptor binding / copper ion transport / positive regulation of keratinocyte migration / cellular response to L-leucine / MTOR signalling / Amino acids regulate mTORC1 / cellular response to nutrient / energy reserve metabolic process / Energy dependent regulation of mTOR by LKB1-AMPK / nucleus localization / ruffle organization / protein-containing complex localization / negative regulation of cell size / cellular response to osmotic stress / anoikis / cardiac muscle cell development / negative regulation of protein localization to nucleus / positive regulation of transcription by RNA polymerase III / regulation of myelination / negative regulation of calcineurin-NFAT signaling cascade / negative regulation of microtubule polymerization / Macroautophagy / regulation of cell size / negative regulation of macroautophagy / lysosome organization / positive regulation of oligodendrocyte differentiation / FK506 binding / positive regulation of actin filament polymerization / positive regulation of myotube differentiation / behavioral response to pain / TOR signaling / oligodendrocyte differentiation / androgen receptor signaling pathway / mTORC1-mediated signalling / Constitutive Signaling by AKT1 E17K in Cancer / germ cell development / cellular response to nutrient levels / CD28 dependent PI3K/Akt signaling / positive regulation of translational initiation / positive regulation of phosphoprotein phosphatase activity / neuronal action potential / HSF1-dependent transactivation / regulation of macroautophagy / positive regulation of epithelial to mesenchymal transition / endomembrane system / Attenuation phase / 'de novo' pyrimidine nucleobase biosynthetic process / response to amino acid / positive regulation of lamellipodium assembly / phagocytic vesicle / axonal growth cone / chaperone-mediated protein folding / positive regulation of lipid biosynthetic process / regulation of cellular response to heat / heart morphogenesis / embryo implantation / cardiac muscle contraction / positive regulation of stress fiber assembly / cytoskeleton organization / cellular response to amino acid starvation / heat shock protein binding / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / T cell costimulation / cellular response to starvation / positive regulation of glycolytic process / response to nutrient levels / ESR-mediated signaling / negative regulation of autophagy / response to nutrient / post-embryonic development / positive regulation of translation / VEGFR2 mediated vascular permeability / peptidylprolyl isomerase / Regulation of PTEN gene transcription
Similarity search - Function
FKBP12-rapamycin binding domain / Tetratricopeptide repeat 2 / Tetratricopeptide repeat / Domain of unknown function DUF3385, target of rapamycin protein / Domain of unknown function (DUF3385) / Domain of unknown function / FKBP12-rapamycin binding domain / Serine/threonine-protein kinase TOR / FKBP12-rapamycin binding domain superfamily / FKBP12-rapamycin binding domain ...FKBP12-rapamycin binding domain / Tetratricopeptide repeat 2 / Tetratricopeptide repeat / Domain of unknown function DUF3385, target of rapamycin protein / Domain of unknown function (DUF3385) / 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. / Tetratricopeptide repeat 1 / Chitinase A; domain 3 - #40 / Tetratricopeptide repeat / 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 / 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 / TPR repeat region circular profile. / 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 FKBP4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.8 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 FKBP4
B: Serine/threonine-protein kinase mTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,4114
Polymers27,4002
Non-polymers1,0102
Water2,720151
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2470 Å2
ΔGint-29 kcal/mol
Surface area11170 Å2
MethodPISA
Unit cell
Length a, b, c (Å)58.523, 62.989, 70.142
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 FKBP4 / PPIase FKBP4 / 51 kDa FK506-binding protein / FKBP51 / 52 kDa FK506-binding protein / 52 kDa FKBP / ...PPIase FKBP4 / 51 kDa FK506-binding protein / FKBP51 / 52 kDa FK506-binding protein / 52 kDa FKBP / FKBP-52 / 59 kDa immunophilin / p59 / FK506-binding protein 4 / FKBP-4 / FKBP59 / HSP-binding immunophilin / HBI / Immunophilin FKBP52 / Rotamase / Peptidyl-prolyl cis-trans isomerase FKBP4 / N-terminally processed


Mass: 15652.896 Da / Num. of mol.: 1 / Fragment: Fk1 domain, UNP residues 1-140
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FKBP4, FKBP52 / Plasmid: pProEx-Hta / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q02790, 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 / Sirolimus


Mass: 914.172 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C51H79NO13 / Comment: immunosuppressant, antibiotic*YM
#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 151 / 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: 2.39 Å3/Da / Density % sol: 48.46 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.5
Details: 0.1M BisTris, 1.95M (NH4)2SO4, pH 6.5, 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: 1.8→70.186 Å / Num. all: 24366 / Num. obs: 24366 / % possible obs: 99 % / Redundancy: 3.5 % / Biso Wilson estimate: 30.34 Å2 / Rmerge(I) obs: 0.044 / Rsym value: 0.044 / Net I/σ(I): 16.2
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRsym value% possible all
1.8-1.93.60.352.21263035100.3598.9
1.9-2.013.60.1973.91187433150.19799.3
2.01-2.153.60.1176.31113731190.11799.3
2.15-2.323.50.0779.41043229430.07799.5
2.32-2.553.50.05511.9952627220.05599.6
2.55-2.853.50.04215857724730.04299.8
2.85-3.293.40.03913.6749521920.03999.7
3.29-4.023.30.0413.5607018620.0499
4.02-5.693.30.03317.9464414240.03395.8
5.69-70.1863.10.03218.925338060.03292.9

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation3 Å46.87 Å
Translation3 Å46.87 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: 3FAP

3fap


Resolution: 1.8→19.76 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.947 / WRfactor Rfree: 0.2728 / WRfactor Rwork: 0.2348 / Occupancy max: 1 / Occupancy min: 0.3 / FOM work R set: 0.8625 / SU B: 5.362 / SU ML: 0.084 / SU R Cruickshank DPI: 0.1399 / SU Rfree: 0.1314 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.124 / ESU R Free: 0.12 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2247 1233 5.1 %RANDOM
Rwork0.1883 ---
all0.1901 24338 --
obs0.1901 23105 98.61 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 226.3 Å2 / Biso mean: 40.58 Å2 / Biso min: 19.26 Å2
Baniso -1Baniso -2Baniso -3
1--0.02 Å20 Å20 Å2
2--0.01 Å20 Å2
3---0.01 Å2
Refinement stepCycle: LAST / Resolution: 1.8→19.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1705 0 70 151 1926
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0221850
X-RAY DIFFRACTIONr_angle_refined_deg1.2871.9962503
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.865221
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.76623.92479
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.79615306
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.345159
X-RAY DIFFRACTIONr_chiral_restr0.0850.2262
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.021403
X-RAY DIFFRACTIONr_nbd_refined0.2040.2859
X-RAY DIFFRACTIONr_nbtor_refined0.3070.21278
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1390.2130
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1690.225
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1480.217
X-RAY DIFFRACTIONr_mcbond_it0.6911.51123
X-RAY DIFFRACTIONr_mcangle_it0.93321748
X-RAY DIFFRACTIONr_scbond_it1.6543833
X-RAY DIFFRACTIONr_scangle_it2.464.5755
LS refinement shellResolution: 1.8→1.846 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.324 96 -
Rwork0.253 1657 -
all-1753 -
obs--98.59 %
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)
113.66376.0963-2.079814.71198.072520.1436-0.2301-0.1265-0.10870.95160.0379-1.80111.19411.16920.1922-0.05780.0334-0.083-0.00190.01180.16324.428-1.7703-10.3185
23.04140.27421.38413.6461-1.01794.54770.09150.4373-0.1358-0.16620.0209-0.61860.41520.4-0.1124-0.10190.0460.0039-0.0967-0.0336-0.056416.9787-9.6257-17.4278
35.26550.02870.25252.3199-0.25295.84140.06530.4592-0.1323-0.06920.0716-0.25150.37390.0301-0.1368-0.1235-0.0061-0.0058-0.1270.0181-0.148312.5071-7.3506-16.8163
43.01940.650.36663.03680.77729.73040.1049-0.0055-0.2360.1230.0057-0.09650.7224-0.5337-0.1106-0.1316-0.0223-0.0502-0.1230.0104-0.127911.0533-10.0272-10.7226
59.48780.50982.55895.0127-1.68658.8243-0.02110.37630.49710.05320.06030.7613-0.2389-0.4068-0.0392-0.11240.02960.0536-0.13760.06560.0569-11.4001-7.1863-13.8277
642.626-6.621432.46564.57867.893571.8691.05812.7787-1.59390.7081-0.87121.3969-1.0863-2.4896-0.1868-0.08390.0809-0.08570.6316-0.22650.5619-23.3301-14.2279-25.146
74.0641-0.27581.16414.9007-5.203613.4649-0.05740.4993-0.1352-0.20470.12240.43030.3178-0.2313-0.0649-0.1309-0.02710.0244-0.1061-0.0187-0.076-10.3363-19.5417-14.0426
88.55030.75240.418211.502-4.486913.9717-0.19351.32210.2896-0.8330.16620.2121-0.19370.78530.0273-0.0942-0.082-0.01110.10960.0427-0.143-4.9983-12.234-22.221
912.15613.67620.4924.24150.43072.3710.06120.18930.26810.0990.05410.12010.0091-0.1404-0.1152-0.1529-0.0075-0.0131-0.10780.0356-0.19942.9323-8.5738-13.1352
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A19 - 29
2X-RAY DIFFRACTION2A30 - 69
3X-RAY DIFFRACTION3A70 - 114
4X-RAY DIFFRACTION4A115 - 139
5X-RAY DIFFRACTION5B2019 - 2056
6X-RAY DIFFRACTION6B2057 - 2067
7X-RAY DIFFRACTION7B2068 - 2098
8X-RAY DIFFRACTION8B2099 - 2114
9X-RAY DIFFRACTION9A201

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