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- PDB-5k0x: Crystal structure of the catalytic domain of the proto-oncogene t... -

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Basic information

Entry
Database: PDB / ID: 5k0x
TitleCrystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC2541
ComponentsTyrosine-protein kinase Mer
KeywordsTransferase/Transferase Inhibitor / Macrocyclic / Drug Design / Fibrinolytic Agents / Protein Kinase Inhibitors / Proto-Oncogene Proteins / Pyrimidines / Receptor Protein-Tyrosine Kinases / Structure-Activity Relationship / Thrombosis / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


negative regulation of leukocyte apoptotic process / negative regulation of lymphocyte activation / neutrophil clearance / natural killer cell differentiation / secretion by cell / negative regulation of cytokine production / vagina development / photoreceptor outer segment / phagocytosis / transmembrane receptor protein tyrosine kinase activity ...negative regulation of leukocyte apoptotic process / negative regulation of lymphocyte activation / neutrophil clearance / natural killer cell differentiation / secretion by cell / negative regulation of cytokine production / vagina development / photoreceptor outer segment / phagocytosis / transmembrane receptor protein tyrosine kinase activity / substrate adhesion-dependent cell spreading / positive regulation of phagocytosis / cell surface receptor protein tyrosine kinase signaling pathway / Cell surface interactions at the vascular wall / establishment of localization in cell / receptor protein-tyrosine kinase / platelet activation / cell migration / nervous system development / cell-cell signaling / retina development in camera-type eye / spermatogenesis / cell surface receptor signaling pathway / protein phosphorylation / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / extracellular space / ATP binding / plasma membrane / cytoplasm
Similarity search - Function
Immunoglobulin / Immunoglobulin domain / Immunoglobulin domain / Fibronectin type III domain / : / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Tyrosine-protein kinase, catalytic domain ...Immunoglobulin / Immunoglobulin domain / Immunoglobulin domain / Fibronectin type III domain / : / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Immunoglobulin subtype / Immunoglobulin / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-K0X / Tyrosine-protein kinase Mer
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.231 Å
AuthorsMcIver, A.L. / Zhang, W. / Liu, Q. / Jiang, X. / Stashko, M.A. / Nichols, J. / Miley, M.J. / Norris-Drouin, J. / Machius, M. / DeRyckere, D. ...McIver, A.L. / Zhang, W. / Liu, Q. / Jiang, X. / Stashko, M.A. / Nichols, J. / Miley, M.J. / Norris-Drouin, J. / Machius, M. / DeRyckere, D. / Wood, E. / Graham, D.K. / Earp, H.S. / Kireev, D. / Frye, S.V. / Wang, X.
CitationJournal: ChemMedChem / Year: 2017
Title: Discovery of Macrocyclic Pyrimidines as MerTK-Specific Inhibitors.
Authors: McIver, A.L. / Zhang, W. / Liu, Q. / Jiang, X. / Stashko, M.A. / Nichols, J. / Miley, M.J. / Norris-Drouin, J. / Machius, M. / DeRyckere, D. / Wood, E. / Graham, D.K. / Earp, H.S. / Kireev, ...Authors: McIver, A.L. / Zhang, W. / Liu, Q. / Jiang, X. / Stashko, M.A. / Nichols, J. / Miley, M.J. / Norris-Drouin, J. / Machius, M. / DeRyckere, D. / Wood, E. / Graham, D.K. / Earp, H.S. / Kireev, D. / Frye, S.V. / Wang, X.
History
DepositionMay 17, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 22, 2017Provider: repository / Type: Initial release
Revision 1.1Sep 27, 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: Tyrosine-protein kinase Mer
B: Tyrosine-protein kinase Mer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,8999
Polymers71,7792
Non-polymers1,1207
Water1,71195
1
A: Tyrosine-protein kinase Mer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,4675
Polymers35,8891
Non-polymers5784
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase Mer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,4324
Polymers35,8891
Non-polymers5423
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.671, 91.599, 69.769
Angle α, β, γ (deg.)90.000, 102.370, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Tyrosine-protein kinase Mer / Proto-oncogene c-Mer / Receptor tyrosine kinase MerTK


Mass: 35889.434 Da / Num. of mol.: 2 / Fragment: catalytic domain, UNP residues 570-864
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MERTK, MER / Production host: Escherichia coli (E. coli)
References: UniProt: Q12866, receptor protein-tyrosine kinase
#2: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-K0X / (7S)-7-amino-N-[(4-fluorophenyl)methyl]-8-oxo-2,9,16,18,21-pentaazabicyclo[15.3.1]henicosa-1(21),17,19-triene-20-carboxamide / UNC2541


Mass: 471.571 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C24H34FN7O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 95 / 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: 2.25 Å3/Da / Density % sol: 45.26 %
Crystal growTemperature: 286 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: Protein at 32.5 mg/mL (in 20 mM Tris pH 8.0, 500 mM NaCl, 2mM BME) was incubated overnight with inhibitor at 2.5 mM final concentration, and then was mixed 1:1 with crystallization solution ...Details: Protein at 32.5 mg/mL (in 20 mM Tris pH 8.0, 500 mM NaCl, 2mM BME) was incubated overnight with inhibitor at 2.5 mM final concentration, and then was mixed 1:1 with crystallization solution (27-33% (v/v) Peg 400, 200 mM MgCl2, 100 mM Tris pH 8.5).

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-BM / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Dec 12, 2012
RadiationMonochromator: Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.23→50 Å / Num. obs: 30743 / % possible obs: 99.9 % / Observed criterion σ(F): -3 / Observed criterion σ(I): -3 / Redundancy: 4.2 % / Biso Wilson estimate: 29.5 Å2 / Rmerge(I) obs: 0.076 / Net I/σ(I): 8.8
Reflection shellResolution: 2.23→2.27 Å / Redundancy: 4 % / Rmerge(I) obs: 0.661 / Mean I/σ(I) obs: 2 / % possible all: 99

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Processing

Software
NameVersionClassification
PHENIX1.10.1_2155refinement
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3BRB

3brb


Resolution: 2.231→27.864 Å / SU ML: 0.23 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 26.63
RfactorNum. reflection% reflection
Rfree0.239 2000 7.6 %
Rwork0.1848 --
obs0.189 26319 84.99 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 178.81 Å2 / Biso mean: 48.6854 Å2 / Biso min: 5.37 Å2
Refinement stepCycle: final / Resolution: 2.231→27.864 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4112 0 141 95 4348
Biso mean--49.38 32.11 -
Num. residues----512
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0144304
X-RAY DIFFRACTIONf_angle_d1.2965813
X-RAY DIFFRACTIONf_chiral_restr0.059647
X-RAY DIFFRACTIONf_plane_restr0.008727
X-RAY DIFFRACTIONf_dihedral_angle_d15.0382630
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.2307-2.28650.2758600.178672978936
2.2865-2.34830.2929870.17861056114351
2.3483-2.41740.25541020.19031242134462
2.4174-2.49530.27011210.20211479160072
2.4953-2.58450.24661340.20841627176180
2.5845-2.68790.26491530.20291858201191
2.6879-2.81010.27941600.20841952211298
2.8101-2.95810.24631680.213720362204100
2.9581-3.14320.27091680.206820382206100
3.1432-3.38550.25451700.20720632233100
3.3855-3.72550.26211680.182920412209100
3.7255-4.26290.23971680.162920552223100
4.2629-5.36450.19441690.152420512220100
5.3645-27.86640.1981720.181820922264100

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