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- PDB-7uy0: Crystal structure of human Fgr tyrosine kinase in complex with A-... -

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Basic information

Entry
Database: PDB / ID: 7uy0
TitleCrystal structure of human Fgr tyrosine kinase in complex with A-419259
Components(Tyrosine-protein kinase ...) x 2
KeywordsTRANSFERASE / Fgr / A-419259 / 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
PHOSPHATE ION / Chem-VSE / Tyrosine-protein kinase Fgr
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.55 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 1.3Nov 13, 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
B: Tyrosine-protein kinase Fgr
hetero molecules


Theoretical massNumber of molelcules
Total (without water)106,13213
Polymers104,5592
Non-polymers1,57311
Water90150
1
A: Tyrosine-protein kinase Fgr
hetero molecules


Theoretical massNumber of molelcules
Total (without water)52,9445
Polymers52,2411
Non-polymers7024
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase Fgr
hetero molecules


Theoretical massNumber of molelcules
Total (without water)53,1888
Polymers52,3171
Non-polymers8717
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)49.430, 112.090, 213.730
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Tyrosine-protein kinase ... , 2 types, 2 molecules AB

#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: 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: 52317.375 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

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Non-polymers , 5 types, 61 molecules

#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-VSE / 7-[trans-4-(4-methylpiperazin-1-yl)cyclohexyl]-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine


Mass: 482.620 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H34N6O / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cl
#6: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 50 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.96 Å3/Da / Density % sol: 58.4 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 7.5
Details: For co-crystallization with A-419259, 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 A-419259 (in 50% DMSO) to a final inhibitor concentration of ...Details: For co-crystallization with A-419259, 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 A-419259 (in 50% DMSO) to a final inhibitor concentration of 120 microM (0.3% DMSO final) and incubated for 30 min at 298 K prior to crystallization setup. Crystals were grown by sitting- and hanging-drop vapor diffusion at 277 K by mixing Fgr/A-419259 in a 1:1 ratio with the mother liquor (0.2 M sodium/potassium phosphate, 0.1 M Bis-Tris propane, pH 7.5, and 16% PEG 3350). To promote crystal growth, crystal seeds from initial needle-like crystals were added to the crystallization drops

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.03326 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Nov 9, 2018
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.03326 Å / Relative weight: 1
ReflectionResolution: 2.55→77.346 Å / Num. obs: 39772 / % possible obs: 100 % / Redundancy: 12.61 % / Biso Wilson estimate: 65.511 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.12 / Rrim(I) all: 0.125 / Χ2: 0.888 / Net I/σ(I): 13.4 / Num. measured all: 501528 / Scaling rejects: 71
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
2.55-2.6212.9091.182.0737657291729170.771.227100
2.62-2.6912.690.9492.5735125276827680.8120.988100
2.69-2.7712.7310.8043.0935506279027890.8710.836100
2.77-2.8512.9340.6353.9634184264326430.9210.661100
2.85-2.9412.8450.4945.1533269259025900.9480.514100
2.94-3.0512.750.3866.3532156252225220.9710.402100
3.05-3.1612.8430.2918.3230747239423940.9820.303100
3.16-3.2912.6180.21710.9329880236823680.9890.226100
3.29-3.4412.5890.17613.3827847221222120.9910.183100
3.44-3.6112.9540.1417.0128200217721770.9940.146100
3.61-3.812.5410.12418.725785205620560.9950.129100
3.8-4.0312.5330.10521.6624100192319230.9960.11100
4.03-4.3112.380.09224.4122668183118310.9970.096100
4.31-4.6612.580.08625.7421764173017300.9970.09100
4.66-5.112.7380.08326.7220342159715970.9970.086100
5.1-5.712.2460.08525.0417622143914390.9970.089100
5.7-6.5811.8130.0826.0215215128812880.9970.083100
6.58-8.0612.3220.0728.613751111611160.9980.073100
8.06-11.411.3410.05831.9299918818810.9980.061100
11.4-77.34610.770.05632.6957195335310.9970.05999.6

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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: 2.55→77.346 Å / SU ML: 0.33 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 22.82 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2229 2000 5.03 %
Rwork0.1865 37766 -
obs0.1883 39766 99.97 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 172.43 Å2 / Biso mean: 71.1545 Å2 / Biso min: 33.05 Å2
Refinement stepCycle: final / Resolution: 2.55→77.346 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7168 0 104 50 7322
Biso mean--67.04 58.03 -
Num. residues----896
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / % reflection obs: 100 %

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork
2.55-2.61380.28641410.25712666
2.6138-2.68450.30291380.24972607
2.6845-2.76350.29251420.24282681
2.7635-2.85270.27811400.26572643
2.8527-2.95460.27861410.25182674
2.9546-3.07290.30011410.2422653
3.0729-3.21280.28411410.2312667
3.2128-3.38220.22851420.21512672
3.3822-3.59410.2891420.20832695
3.5941-3.87160.23321430.18852700
3.8716-4.26120.20491440.15792694
4.2612-4.87770.17311440.14812745
4.8777-6.1450.18721470.172767
6.145-77.3460.19011540.15792902
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)
11.6212-0.0460.56041.7729-1.63551.45810.15750.12970.1209-0.1651-0.22920.21240.2869-0.3247-00.7146-0.039-0.1420.5904-0.0360.564525.2084-8.6172-39.906
21.65750.03521.02342.6449-1.66722.2279-0.09740.0822-0.1301-0.5857-0.0105-0.46290.31660.00940.00010.6627-0.04940.02310.4584-0.00390.515636.7579-30.5842-32.9088
32.49510.02571.16421.83620.4933.0825-0.0097-0.10050.1328-0.0378-0.01260.1304-0.19240.05-0.00010.3375-0.05450.03360.4129-0.03640.407942.12840.563-17.3161
40.74591.2650.34411.85351.10291.93290.1057-0.057-0.29530.30290.1844-0.4520.23740.68640.00010.48320.0664-0.07060.6674-0.03750.593956.8008-14.0266-11.7208
51.07020.66150.60110.88-0.31211.3208-0.01650.16250.35370.23280.10220.7011-0.4802-0.090200.86580.24620.29840.65640.23760.909420.042824.585735.0004
63.03140.39110.18521.13090.53772.97660.25840.0005-0.1590.1538-0.08620.0616-0.0872-0.2473-00.570.08830.14580.55630.09150.615124.45513.854148.6981
70.43910.3640.03510.78380.44071.36810.53710.11740.5394-0.4807-0.3013-0.3893-0.6184-0.19260.00020.69870.14390.17560.52470.16250.932740.459923.528918.0064
81.2818-1.2147-0.82653.3373-0.84711.54070.12290.05540.329-0.01450.0273-0.0779-0.3264-0.16640.00890.54540.06340.09690.53610.07010.53839.72629.856921.3724
90.0162-0.134-0.17050.0174-0.3130.8395-0.01240.2503-0.1673-0.14070.03460.042-0.2847-0.1194-00.64190.00120.06110.70330.0190.555148.2201-0.12775.5991
101.5458-0.95470.68852.20630.05111.976-0.09780.4434-0.1215-0.01270.0224-0.02130.3360.22430.00090.53210.07870.0660.5043-0.01010.510950.791-9.263520.8694
11-0.3004-0.7832-1.8189-0.77080.47930.8768-0.3870.1543-0.2210.10620.09770.27750.5508-0.1509-0.01090.7036-0.03390.16860.6180.00640.645134.0552-10.211932.0067
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 84 through 154 )A84 - 154
2X-RAY DIFFRACTION2chain 'A' and (resid 155 through 252 )A155 - 252
3X-RAY DIFFRACTION3chain 'A' and (resid 253 through 440 )A253 - 440
4X-RAY DIFFRACTION4chain 'A' and (resid 441 through 531 )A441 - 531
5X-RAY DIFFRACTION5chain 'B' and (resid 84 through 154 )B84 - 154
6X-RAY DIFFRACTION6chain 'B' and (resid 155 through 252 )B155 - 252
7X-RAY DIFFRACTION7chain 'B' and (resid 253 through 286 )B253 - 286
8X-RAY DIFFRACTION8chain 'B' and (resid 287 through 410 )B287 - 410
9X-RAY DIFFRACTION9chain 'B' and (resid 411 through 440 )B411 - 440
10X-RAY DIFFRACTION10chain 'B' and (resid 441 through 498 )B441 - 498
11X-RAY DIFFRACTION11chain 'B' and (resid 499 through 531 )B499 - 531

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