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- PDB-7uy3: Crystal structure of human Fgr tyrosine kinase in complex with TL02-59 -

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Basic information

Entry
Database: PDB / ID: 7uy3
TitleCrystal structure of human Fgr tyrosine kinase in complex with TL02-59
ComponentsTyrosine-protein kinase Fgr
KeywordsTRANSFERASE / Fgr / TL02-59 / SIGNALING PROTEIN / kinase
Function / homology
Function and homology information


negative regulation of natural killer cell activation / immune response-regulating cell surface receptor signaling pathway / regulation of protein kinase activity / positive regulation of mast cell degranulation / Fc-gamma receptor I complex binding / regulation of phagocytosis / aggresome / immunoglobulin receptor binding / skeletal system morphogenesis / Platelet sensitization by LDL ...negative regulation of natural killer cell activation / immune response-regulating cell surface receptor signaling pathway / regulation of protein kinase activity / positive regulation of mast cell degranulation / Fc-gamma receptor I complex binding / regulation of phagocytosis / aggresome / immunoglobulin receptor binding / skeletal system morphogenesis / Platelet sensitization by LDL / regulation of innate immune response / bone mineralization / Fc-gamma receptor signaling pathway involved in phagocytosis / FCGR activation / phosphotyrosine residue binding / FCGR3A-mediated IL10 synthesis / cell surface receptor protein tyrosine kinase signaling pathway / peptidyl-tyrosine phosphorylation / positive regulation of cytokine production / integrin-mediated signaling pathway / non-membrane spanning protein tyrosine kinase activity / FCGR3A-mediated phagocytosis / non-specific protein-tyrosine kinase / negative regulation of inflammatory response to antigenic stimulus / mitochondrial intermembrane space / response to virus / ruffle membrane / regulation of cell shape / actin cytoskeleton / protein autophosphorylation / protein tyrosine kinase activity / secretory granule lumen / cell differentiation / protein phosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / mitochondrial inner membrane / defense response to Gram-positive bacterium / positive regulation of cell migration / signaling receptor binding / innate immune response / Neutrophil degranulation / protein kinase binding / extracellular exosome / extracellular region / ATP binding / plasma membrane / cytosol
Similarity search - Function
Tyrosine-protein kinase Fgr, SH2 domain / : / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH2 domain superfamily / SH3-like domain superfamily ...Tyrosine-protein kinase Fgr, SH2 domain / : / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-OJL / PHOSPHATE ION / Tyrosine-protein kinase Fgr
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.99 Å
AuthorsDu, S. / Alvarado, J.J. / Smithgall, T.E.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)CA233576 United States
CitationJournal: Structure / Year: 2022
Title: ATP-site inhibitors induce unique conformations of the acute myeloid leukemia-associated Src-family kinase, Fgr.
Authors: Du, S. / Alvarado, J.J. / Wales, T.E. / Moroco, J.A. / Engen, J.R. / Smithgall, T.E.
History
DepositionMay 6, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 28, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 25, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.3Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase Fgr
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,1956
Polymers52,2411
Non-polymers9545
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, SEC-MALS
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)151.285, 151.285, 130.518
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number179
Space group name H-MP6522

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Components

#1: Protein Tyrosine-protein kinase Fgr / Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene homolog / Proto-oncogene c-Fgr / p55-Fgr / ...Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene homolog / Proto-oncogene c-Fgr / p55-Fgr / p58-Fgr / p58c-Fgr


Mass: 52241.254 Da / Num. of mol.: 1 / Mutation: Q528E, P529E, G530I, D531P
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: FGR, SRC2 / Plasmid: pFastBac1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P09769, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-OJL / 3-[(6,7-dimethoxyquinazolin-4-yl)oxy]-N-{4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}-4-methylbenzamide


Mass: 609.639 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H34F3N5O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
Has ligand of interestY
Has protein modificationY

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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: 4.2 Å3/Da / Density % sol: 70.7 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 7.5
Details: For co-crystallization with TL02-59, Fgr (3.2 mg/mL in 20 mM Tris-HCl, pH 8.3, 100 mM NaCl, and 2 mM TCEP) was mixed with 10 mM TL02-59 (in 100% DMSO) to a final concentration of 120 microM ...Details: For co-crystallization with TL02-59, Fgr (3.2 mg/mL in 20 mM Tris-HCl, pH 8.3, 100 mM NaCl, and 2 mM TCEP) was mixed with 10 mM TL02-59 (in 100% DMSO) to a final concentration of 120 microM (0.6% DMSO final) and incubated for thirty minutes at 298 K. Diffraction quality crystals were grown by sitting- and hanging-drop vapor diffusion at 277 K by mixing Fgr/TL02-59 in a 1:1 ratio with the mother liquor (0.1 M HEPES, pH 7.5, 0.8 M sodium phosphate, 0.8 M potassium phosphate and 1% 1,2-butanediol)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 0.9757 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Mar 29, 2018
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9757 Å / Relative weight: 1
ReflectionResolution: 2.99→46.233 Å / Num. obs: 33705 / % possible obs: 99.9 % / Redundancy: 10.954 % / Biso Wilson estimate: 84.007 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.125 / Rrim(I) all: 0.131 / Χ2: 0.905 / Net I/σ(I): 11.89
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured obsNum. possibleNum. unique obsCC1/2Rrim(I) all% possible all
2.99-3.0711.230.8042.0714722131313110.9090.8499.8
3.07-3.1510.9520.6092.7814271130513030.9310.63799.8
3.15-3.2410.2270.5013.6212712124412430.9560.52699.9
3.24-3.3410.9140.3774.7513435123112310.9780.395100
3.34-3.4511.6450.2846.6713916119611950.9870.29699.9
3.45-3.5711.7530.2238.113492114811480.9920.232100
3.57-3.7111.5740.1929.6512917111711160.9930.299.9
3.71-3.8611.4220.16411.4712279107610750.9950.1799.9
3.86-4.0311.3310.14513.6411637102810270.9940.1599.9
4.03-4.2311.0780.12915.03110569989980.9950.134100
4.23-4.4610.7480.11317.3101789479470.9960.117100
4.46-4.7310.0880.10717.590498998970.9960.11299.8
4.73-5.0510.370.10318.7288258518510.9960.108100
5.05-5.4611.4720.10419.6990867927920.9960.107100
5.46-5.9811.2490.10319.7383477427420.9960.107100
5.98-6.6911.0240.120.3673426676660.9950.10499.9
6.69-7.7210.5670.09221.5464676126120.9950.097100
7.72-9.469.1430.08422.0847455195190.9950.089100
9.46-13.3710.1110.0824.0841964154150.9980.084100
13.37-46.2338.8040.07921.9722012612500.9960.08495.8

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Processing

Software
NameVersionClassification
PHENIX1.14_3260refinement
XDSdata reduction
XSCALEdata scaling
PDB_EXTRACT3.27data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2SRC

2src


Resolution: 2.99→46.233 Å / SU ML: 0.41 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 26.18 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2473 3368 9.99 %
Rwork0.2031 30337 -
obs0.2074 33705 99.67 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 232.45 Å2 / Biso mean: 104.6638 Å2 / Biso min: 53.78 Å2
Refinement stepCycle: final / Resolution: 2.99→46.233 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3069 0 64 0 3133
Biso mean--101.46 --
Num. residues----386
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.99-3.03220.37071420.3196125999
3.0322-3.07750.42571420.3466126699
3.0775-3.12560.37761370.3259124799
3.1256-3.17680.31291470.30131266100
3.1768-3.23160.27781300.26931263100
3.2316-3.29030.30351440.25751274100
3.2903-3.35360.29441400.25651252100
3.3536-3.4220.29051370.2505126599
3.422-3.49640.2881380.24511267100
3.4964-3.57770.26961450.24071257100
3.5777-3.66710.27731340.23371263100
3.6671-3.76620.22911400.19591266100
3.7662-3.8770.23931440.18341267100
3.877-4.00210.20131410.16461273100
4.0021-4.1450.21871410.17981245100
4.145-4.31090.2111420.17241275100
4.3109-4.50690.22361430.16481271100
4.5069-4.74430.21661330.15961269100
4.7443-5.04120.21981390.16691278100
5.0412-5.42990.23031430.17571258100
5.4299-5.97530.23671410.19981266100
5.9753-6.83750.23651410.20851269100
6.8375-8.60550.2281470.1931268100
8.6055-46.230.27611370.2172125399
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)
12.5096-0.9345-1.34571.4469-1.17363.00280.2222-0.29220.10890.1675-0.0870.1066-0.00090.018-0.00030.86670.09440.0270.7899-0.02320.6982-66.8818-24.043518.3405
20.3407-0.48750.1860.5851-0.21920.06580.4218-0.1505-0.122-0.3962-0.2938-0.0685-0.1098-0.5503-0.01861.2270.1038-0.09680.72170.05990.9387-59.1205-44.451921.1515
32.8692-0.6873-1.75082.28180.13481.1705-0.4078-0.69970.07690.31410.29810.0277-0.08940.40020.00010.81930.19390.04670.65660.00360.6663-39.3266-43.31433.178
41.55771.2888-0.53143.0543-1.41031.7878-0.08660.0481-0.015-0.2883-0.1605-0.33220.23050.5436-0.30120.63720.28480.02740.7951-0.04310.7125-51.8959-16.72125.6669
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 380 through 499 )A380 - 499
2X-RAY DIFFRACTION2chain 'A' and (resid 500 through 531 )A500 - 531
3X-RAY DIFFRACTION3chain 'A' and (resid 139 through 251 )A139 - 251
4X-RAY DIFFRACTION4chain 'A' and (resid 252 through 379 )A252 - 379

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