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- PDB-6m4u: Crystal structure of FKBP-FRB T2098L mutant in complex with rapamycin -

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Basic information

Entry
Database: PDB / ID: 6m4u
TitleCrystal structure of FKBP-FRB T2098L mutant in complex with rapamycin
Components
  • Peptidyl-prolyl cis-trans isomerase FKBP1A
  • Serine/threonine-protein kinase mTOR
KeywordsISOMERASE / Rapamycin / complex / kinase
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 / T-helper 1 cell lineage commitment / positive regulation of pentose-phosphate shunt / regulation of locomotor rhythm / 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 / T-helper 1 cell lineage commitment / positive regulation of pentose-phosphate shunt / regulation of locomotor rhythm / positive regulation of wound healing, spreading of epidermal cells / TORC2 signaling / TORC2 complex / regulation of membrane permeability / cellular response to leucine starvation / macrolide binding / heart valve morphogenesis / activin receptor binding / negative regulation of lysosome organization / TFIIIC-class transcription factor complex binding / TORC1 complex / positive regulation of transcription of nucleolar large rRNA by RNA polymerase I / calcineurin-NFAT signaling cascade / voluntary musculoskeletal movement / regulation of osteoclast differentiation / regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion / cytoplasmic side of membrane / RNA polymerase III type 3 promoter sequence-specific DNA binding / positive regulation of keratinocyte migration / transforming growth factor beta receptor binding / regulation of lysosome organization / Amino acids regulate mTORC1 / TGFBR1 LBD Mutants in Cancer / cellular response to L-leucine / MTOR signalling / cellular response to nutrient / type I transforming growth factor beta receptor binding / regulation of autophagosome assembly / Energy dependent regulation of mTOR by LKB1-AMPK / TORC1 signaling / energy reserve metabolic process / negative regulation of activin receptor signaling pathway / ruffle organization / serine/threonine protein kinase complex / negative regulation of cell size / heart trabecula formation / cellular response to methionine / I-SMAD binding / positive regulation of ubiquitin-dependent protein catabolic process / inositol hexakisphosphate binding / cellular response to osmotic stress / signaling receptor inhibitor activity / regulation of amyloid precursor protein catabolic process / anoikis / terminal cisterna / ryanodine receptor complex / negative regulation of protein localization to nucleus / cardiac muscle cell development / negative regulation of calcineurin-NFAT signaling cascade / regulation of myelination / positive regulation of transcription by RNA polymerase III / 'de novo' protein folding / positive regulation of actin filament polymerization / negative regulation of macroautophagy / ventricular cardiac muscle tissue morphogenesis / Macroautophagy / regulation of cell size / FK506 binding / positive regulation of myotube differentiation / Constitutive Signaling by AKT1 E17K in Cancer / oligodendrocyte differentiation / germ cell development / behavioral response to pain / TGF-beta receptor signaling activates SMADs / TOR signaling / mTORC1-mediated signalling / positive regulation of oligodendrocyte differentiation / positive regulation of translational initiation / Calcineurin activates NFAT / regulation of ryanodine-sensitive calcium-release channel activity / CD28 dependent PI3K/Akt signaling / response to amino acid / HSF1-dependent transactivation / regulation of macroautophagy / regulation of immune response / 'de novo' pyrimidine nucleobase biosynthetic process / cellular response to nutrient levels / vascular endothelial cell response to laminar fluid shear stress / neuronal action potential / positive regulation of lipid biosynthetic process / positive regulation of epithelial to mesenchymal transition / heart morphogenesis / regulation of cellular response to heat / positive regulation of lamellipodium assembly / supramolecular fiber organization / cardiac muscle contraction / phagocytic vesicle / positive regulation of stress fiber assembly / T cell costimulation / sarcoplasmic reticulum membrane / calcium channel regulator activity / cytoskeleton organization / endomembrane system / 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 domain profile. / FKBP-type peptidyl-prolyl cis-trans isomerase / FKBP-type peptidyl-prolyl cis-trans isomerase domain / 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: 2.2 Å
AuthorsKikuchi, M. / Wu, D. / Inoue, T. / Umehara, T.
CitationJournal: Nat.Methods / Year: 2020
Title: Rational design and implementation of a chemically inducible heterotrimerization system.
Authors: Wu, H.D. / Kikuchi, M. / Dagliyan, O. / Aragaki, A.K. / Nakamura, H. / Dokholyan, N.V. / Umehara, T. / Inoue, T.
History
DepositionMar 9, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Aug 26, 2020Provider: repository / Type: Initial release
Revision 2.0Sep 2, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations / Source and taxonomy / Structure summary
Category: atom_site / entity ...atom_site / entity / entity_name_com / entity_src_gen / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_struct_conn_angle / struct_asym / struct_conn / struct_ref / struct_ref_seq / struct_ref_seq_dif / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_entity_id / _atom_site.type_symbol / _entity.pdbx_description / _entity_src_gen.gene_src_common_name / _entity_src_gen.pdbx_gene_src_gene / _entity_src_gen.pdbx_gene_src_ncbi_taxonomy_id / _entity_src_gen.pdbx_gene_src_scientific_name / _pdbx_nonpoly_scheme.auth_mon_id / _pdbx_nonpoly_scheme.auth_seq_num / _pdbx_nonpoly_scheme.entity_id / _pdbx_nonpoly_scheme.mon_id / _pdbx_nonpoly_scheme.pdb_mon_id / _pdbx_nonpoly_scheme.pdb_seq_num / _pdbx_nonpoly_scheme.pdb_strand_id / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _struct_asym.entity_id / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_ref.db_code / _struct_ref.pdbx_align_begin / _struct_ref.pdbx_db_accession / _struct_ref_seq.db_align_beg / _struct_ref_seq.db_align_end / _struct_ref_seq.pdbx_db_accession / _struct_ref_seq_dif.pdbx_seq_db_accession_code / _struct_ref_seq_dif.pdbx_seq_db_seq_num / _struct_site.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_seq_id / _struct_site_gen.auth_asym_id / _struct_site_gen.auth_seq_id / _struct_site_gen.label_asym_id
Revision 2.1Sep 16, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 2.2Nov 29, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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 FKBP1A
B: Serine/threonine-protein kinase mTOR
E: Peptidyl-prolyl cis-trans isomerase FKBP1A
F: Serine/threonine-protein kinase mTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)50,20228
Polymers47,1184
Non-polymers3,08424
Water5,549308
1
A: Peptidyl-prolyl cis-trans isomerase FKBP1A
B: Serine/threonine-protein kinase mTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,13815
Polymers23,5592
Non-polymers1,57913
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
E: Peptidyl-prolyl cis-trans isomerase FKBP1A
F: Serine/threonine-protein kinase mTOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,06413
Polymers23,5592
Non-polymers1,50511
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)57.034, 67.419, 69.793
Angle α, β, γ (deg.)90.00, 107.20, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 2 types, 4 molecules AEBF

#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: 12111.834 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FKBP1A, FKBP1, FKBP12 / Production host: Escherichia coli (E. coli) / References: UniProt: P62942, peptidylprolyl isomerase
#2: Protein Serine/threonine-protein kinase mTOR / Mammalian target of rapamycin / mTOR / Mechanistic target of rapamycin


Mass: 11447.091 Da / Num. of mol.: 2 / Mutation: T2098L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MTOR / Production host: Escherichia coli (E. coli)
References: UniProt: P42345, non-specific serine/threonine protein kinase

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Non-polymers , 5 types, 332 molecules

#3: Chemical ChemComp-RAP / RAPAMYCIN IMMUNOSUPPRESSANT DRUG


Mass: 914.172 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C51H79NO13 / Feature type: SUBJECT OF INVESTIGATION / Comment: immunosuppressant, antibiotic*YM
#4: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: Zn
#5: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: Cl
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 308 / 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: 2.72 Å3/Da / Density % sol: 54.79 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 100 mM cacodylic acid buffer (pH 6.5), 350 mM zinc acetate and 8% (w/v) isopropanol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Sep 12, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→47.45 Å / Num. obs: 24948 / % possible obs: 96.6 % / Redundancy: 6.9 % / CC1/2: 0.995 / Net I/σ(I): 9.7
Reflection shellResolution: 2.2→2.27 Å / Num. unique obs: 2223 / CC1/2: 0.849

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Processing

Software
NameVersionClassification
XDSdata reduction
MOLREPphasing
REFMAC5.8.0258refinement
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1FAP

1fap


Resolution: 2.2→47.4 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.893 / SU B: 7.305 / SU ML: 0.179 / Cross valid method: THROUGHOUT / ESU R: 0.293 / ESU R Free: 0.232
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. SF FILE CONTAINS FRIEDEL PAIRS UNDER I/F_MINUS AND I/F_PLUS COLUMNS.
RfactorNum. reflection% reflectionSelection details
Rfree0.25766 1299 5.2 %RANDOM
Rwork0.19782 ---
obs0.20089 23631 96.54 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 26.727 Å2
Baniso -1Baniso -2Baniso -3
1-0.82 Å2-0 Å2-0.67 Å2
2--0.15 Å20 Å2
3----0.47 Å2
Refinement stepCycle: 1 / Resolution: 2.2→47.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3259 0 157 308 3724
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0020.0133482
X-RAY DIFFRACTIONr_bond_other_d0.0010.0173203
X-RAY DIFFRACTIONr_angle_refined_deg1.1571.6674700
X-RAY DIFFRACTIONr_angle_other_deg1.0751.5787428
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7875402
X-RAY DIFFRACTIONr_dihedral_angle_2_deg26.35720.64203
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.82415582
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.7661525
X-RAY DIFFRACTIONr_chiral_restr0.0420.2428
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.023868
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02763
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.9112.7891620
X-RAY DIFFRACTIONr_mcbond_other0.912.7881619
X-RAY DIFFRACTIONr_mcangle_it1.6094.1792018
X-RAY DIFFRACTIONr_mcangle_other1.6084.182019
X-RAY DIFFRACTIONr_scbond_it0.92.8441862
X-RAY DIFFRACTIONr_scbond_other0.92.8461863
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other1.564.2032683
X-RAY DIFFRACTIONr_long_range_B_refined3.91532.0913945
X-RAY DIFFRACTIONr_long_range_B_other3.64731.8143888
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.2→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.364 91 -
Rwork0.284 1800 -
obs--99.68 %

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