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- PDB-7aay: Crystal structure of MerTK kinase domain in complex with Merestinib -

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Basic information

Entry
Database: PDB / ID: 7aay
TitleCrystal structure of MerTK kinase domain in complex with Merestinib
ComponentsTyrosine-protein kinase Mer
KeywordsTRANSFERASE / tyrosine kinase inhibitor / structure-based drug design / type 2 inhibitor
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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-L1X / Tyrosine-protein kinase Mer
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.87 Å
AuthorsSchimpl, M. / Pflug, A. / McCoull, W. / Nissink, J.W.M. / Overman, R.C. / Rawlins, P.B. / Truman, C. / Underwood, E. / Warwicker, J. / Winter-Holt, J.
CitationJournal: Biochem.J. / Year: 2020
Title: A-loop interactions in Mer tyrosine kinase give rise to inhibitors with two-step mechanism and long residence time of binding.
Authors: Pflug, A. / Schimpl, M. / Nissink, J.W.M. / Overman, R.C. / Rawlins, P.B. / Truman, C. / Underwood, E. / Warwicker, J. / Winter-Holt, J. / McCoull, W.
History
DepositionSep 5, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 28, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 4, 2020Group: Database references / Category: citation / Item: _citation.pdbx_database_id_DOI
Revision 1.2Nov 11, 2020Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.3Dec 9, 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.name
Revision 1.4Jan 31, 2024Group: 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

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Assembly

Deposited unit
A: Tyrosine-protein kinase Mer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,4955
Polymers33,8361
Non-polymers6594
Water2,108117
1


  • Idetical with deposited unit
  • defined by software
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area380 Å2
ΔGint-30 kcal/mol
Surface area13590 Å2
MethodPISA
Unit cell
Length a, b, c (Å)93.119, 130.983, 54.192
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-903-

CL

21A-1090-

HOH

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Components

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


Mass: 33836.223 Da / Num. of mol.: 1 / Fragment: MERTK kinase domain / Mutation: delM659-Q662
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MERTK, MER / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Star
References: UniProt: Q12866, receptor protein-tyrosine kinase
#2: Chemical ChemComp-L1X / N-(3-fluoro-4-{[1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yl]oxy}phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide


Mass: 552.531 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H22F2N6O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 117 / 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: 2.44 Å3/Da / Density % sol: 49.63 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.2 / Details: 0.1M MES pH 6.2, 0.75M LiCl, 23% PEG 6k

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.97949 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Aug 2, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97949 Å / Relative weight: 1
ReflectionResolution: 1.855→46.56 Å / Num. obs: 19081 / % possible obs: 93.8 % / Redundancy: 6.3 % / CC1/2: 0.998 / Rmerge(I) obs: 0.108 / Rpim(I) all: 0.047 / Rrim(I) all: 0.118 / Net I/σ(I): 10.6
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.855-2.0753.50.77633539540.5820.4660.911.463.6
5.965-46.5660.04656839520.9980.020.05128.799.9

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
REFMAC5.8.0135refinement
PDB_EXTRACT3.25data extraction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdbid 3BRB

3brb


Resolution: 1.87→46.56 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.927 / SU B: 4.392 / SU ML: 0.121 / SU R Cruickshank DPI: 0.2165 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.216 / ESU R Free: 0.173 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: REFMAC5
RfactorNum. reflection% reflectionSelection details
Rfree0.2239 960 5 %RANDOM
Rwork0.1953 ---
obs0.1967 18099 68.59 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 105.69 Å2 / Biso mean: 36.09 Å2 / Biso min: 11.65 Å2
Baniso -1Baniso -2Baniso -3
1-0.51 Å20 Å20 Å2
2---0.43 Å20 Å2
3----0.08 Å2
Refinement stepCycle: final / Resolution: 1.87→46.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2151 0 44 117 2312
Biso mean--29.28 34.67 -
Num. residues----273
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0192255
X-RAY DIFFRACTIONr_bond_other_d0.0020.022135
X-RAY DIFFRACTIONr_angle_refined_deg1.3031.9693061
X-RAY DIFFRACTIONr_angle_other_deg0.9434904
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0925273
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.16923.78995
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.61215390
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.2631514
X-RAY DIFFRACTIONr_chiral_restr0.0760.2339
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022504
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02487
LS refinement shellResolution: 1.871→1.92 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.416 3 -
Rwork0.372 36 -
all-39 -
obs--1.95 %

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