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- PDB-7xhy: Crystal structure of MerTK Kinase domain with BMS794833 -

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Basic information

Entry
Database: PDB / ID: 7xhy
TitleCrystal structure of MerTK Kinase domain with BMS794833
ComponentsTyrosine-protein kinase Mer
KeywordsTRANSFERASE / ATP Competitive Inhibitor MerTK-BMS794833 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 / positive regulation of phagocytosis / phagocytosis ...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 / positive regulation of phagocytosis / phagocytosis / transmembrane receptor protein tyrosine kinase activity / substrate adhesion-dependent cell spreading / phosphatidylinositol 3-kinase/protein kinase B signal transduction / establishment of localization in cell / Cell surface interactions at the vascular wall / receptor protein-tyrosine kinase / platelet activation / cell surface receptor protein tyrosine kinase signaling pathway / cell migration / retina development in camera-type eye / cell-cell signaling / nervous system development / spermatogenesis / cell surface receptor signaling pathway / receptor complex / protein phosphorylation / 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 / Tyrosine 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / 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
Similarity search - Domain/homology
Chem-E0X / Tyrosine-protein kinase Mer
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.16 Å
AuthorsKim, J.H. / Lee, B.I.
Funding support Korea, Republic Of, 4items
OrganizationGrant numberCountry
National Research Foundation (NRF, Korea)NRF-2019R1A2C1002545 Korea, Republic Of
National Research Foundation (NRF, Korea)NRF-2018R1A5A2023127 Korea, Republic Of
National Research Foundation (NRF, Korea)2210340 Korea, Republic Of
National Research Foundation (NRF, Korea)1910031 Korea, Republic Of
CitationJournal: Exp.Mol.Med. / Year: 2022
Title: BMS794833 inhibits macrophage efferocytosis by directly binding to MERTK and inhibiting its activity.
Authors: Bae, S.H. / Kim, J.H. / Park, T.H. / Lee, K. / Lee, B.I. / Jang, H.
History
DepositionApr 11, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 30, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase Mer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0717
Polymers34,3821
Non-polymers6896
Water72140
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: small molecule, gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area690 Å2
ΔGint-31 kcal/mol
Surface area14430 Å2
Unit cell
Length a, b, c (Å)92.127, 92.533, 71.435
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Space group name HallC2c2
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z+1/2
#4: -x,-y,z+1/2
#5: x+1/2,y+1/2,z
#6: x+1/2,-y+1/2,-z
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2
Components on special symmetry positions
IDModelComponents
11A-1038-

HOH

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Components

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


Mass: 34381.754 Da / Num. of mol.: 1 / Fragment: Kinase domain / Mutation: K591R, K693R, K702R, K856R
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MERTK, MER / Plasmid: pETduet
Details (production host): MerTK subcloned at MCS1, PTPN1(1-330) subcloned at MCS2
Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q12866, receptor protein-tyrosine kinase
#2: Chemical ChemComp-E0X / ~{N}-[4-(2-azanyl-3-chloranyl-pyridin-4-yl)oxy-3-fluoranyl-phenyl]-5-(4-fluorophenyl)-4-oxidanylidene-1~{H}-pyridine-3-carboxamide


Mass: 468.840 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H15ClF2N4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 40 / Source method: isolated from a natural source / Formula: H2O
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: 2.11 Å3/Da / Density % sol: 41.82 %
Crystal growTemperature: 287 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: Protein concentration 25 mg/mL Protein storage buffer: Tris-HCl pH 8.0, 500 mM NaCl, 1 mM Tris(2-carboxyethyl)phosphine Hydrochloride (TCEP) Mother Liquor: 0.1 M Tris-HCl pH 8.5, 4.3 M NaCl ...Details: Protein concentration 25 mg/mL Protein storage buffer: Tris-HCl pH 8.0, 500 mM NaCl, 1 mM Tris(2-carboxyethyl)phosphine Hydrochloride (TCEP) Mother Liquor: 0.1 M Tris-HCl pH 8.5, 4.3 M NaCl Protein: Reservoir: Apo-Microseed = 300: 300: 100 nL or 400: 400: 100 nL Co-crystalization 2mM compound preincubation: 2Hours in ICE Cryoprotectant solution: 0.1 M Tris-HCl pH 8.5, 2.5 M NaCl, 20% DMSO, 10 mM compounds
PH range: 8.0 - 8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PAL/PLS / Beamline: 11C / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 30, 2021
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.16→50 Å / Num. obs: 16509 / % possible obs: 98.5 % / Observed criterion σ(I): -3 / Redundancy: 6.8 % / CC1/2: 0.985 / CC star: 0.996 / Rpim(I) all: 0.034 / Rrim(I) all: 0.088 / Rsym value: 0.081 / Χ2: 0.594 / Net I/σ(I): 23.2
Reflection shellResolution: 2.16→2.2 Å / Redundancy: 4.7 % / Mean I/σ(I) obs: 2.1 / Num. unique obs: 657 / CC1/2: 0.931 / CC star: 0.982 / Rpim(I) all: 0.218 / Rrim(I) all: 0.528 / Rsym value: 0.478 / Χ2: 0.425 / % possible all: 80.5

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Processing

Software
NameVersionClassification
PHENIX1.18.2_3874refinement
PHASERphasing
HKL-2000data scaling
HKL-2000data reduction
PDB_EXTRACTdata extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7aax

7aax


Resolution: 2.16→38.71 Å / SU ML: 0.2725 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 29.2847
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2523 1648 10 %
Rwork0.208 14829 -
obs0.2125 16477 98.67 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 47.47 Å2
Refinement stepCycle: LAST / Resolution: 2.16→38.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2167 0 41 40 2248
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00812249
X-RAY DIFFRACTIONf_angle_d1.04473038
X-RAY DIFFRACTIONf_chiral_restr0.0592336
X-RAY DIFFRACTIONf_plane_restr0.0066382
X-RAY DIFFRACTIONf_dihedral_angle_d21.7364297
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.16-2.220.32761230.24941092X-RAY DIFFRACTION89.14
2.23-2.30.31391370.25131222X-RAY DIFFRACTION98.76
2.3-2.380.33371360.25361235X-RAY DIFFRACTION99.78
2.38-2.470.31291370.25631216X-RAY DIFFRACTION99.93
2.47-2.590.31691400.23451247X-RAY DIFFRACTION99.93
2.59-2.720.29571380.23141241X-RAY DIFFRACTION100
2.72-2.890.30191340.24331238X-RAY DIFFRACTION100
2.89-3.120.27561370.23141261X-RAY DIFFRACTION99.86
3.12-3.430.25391420.21981243X-RAY DIFFRACTION100
3.43-3.930.23781350.19181260X-RAY DIFFRACTION99.71
3.93-4.940.19681390.17071246X-RAY DIFFRACTION98.3
4.95-38.710.22641500.19061328X-RAY DIFFRACTION98.66

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