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- PDB-7aaz: Crystal structure of MerTK in complex with a type 1.5 aminopyridi... -

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Basic information

Entry
Database: PDB / ID: 7aaz
TitleCrystal structure of MerTK in complex with a type 1.5 aminopyridine inhibitor
ComponentsTyrosine-protein kinase Mer
KeywordsTRANSFERASE / tyrosine kinase inhibitor / structure-based drug design / type 1.5 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 / positive regulation of 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 / phagocytosis / positive regulation of phagocytosis / transmembrane receptor protein tyrosine kinase activity / substrate adhesion-dependent cell spreading / establishment of localization in cell / Cell surface interactions at the vascular wall / receptor protein-tyrosine kinase / platelet activation / cell migration / cell-cell signaling / retina development in camera-type eye / nervous system development / spermatogenesis / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / cell surface receptor signaling pathway / 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 ...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. / Tyrosine-protein kinase, active site / Immunoglobulin subtype / Immunoglobulin / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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-R6K / Tyrosine-protein kinase Mer
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.855 Å
AuthorsPflug, A. / Schimpl, M. / 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 1.0Nov 4, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 11, 2020Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Dec 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 1.3Jan 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)34,91710
Polymers34,0001
Non-polymers9179
Water2,378132
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1140 Å2
ΔGint-48 kcal/mol
Surface area14030 Å2
Unit cell
Length a, b, c (Å)78.629, 78.629, 137.470
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212
Components on special symmetry positions
IDModelComponents
11A-906-

CL

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Components

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


Mass: 34000.359 Da / Num. of mol.: 1 / Fragment: MERTK kinase domain
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-R6K / 2-azanyl-~{N}-[(1~{S},2~{S})-2-[[4-[4-[(4-methylpiperazin-1-yl)methyl]phenyl]phenyl]methoxy]cyclopentyl]-5-(1-methylpyrazol-4-yl)pyridine-3-carboxamide


Mass: 579.735 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H41N7O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 132 / 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: 3.12 Å3/Da / Density % sol: 60.64 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 8.5 / Details: 0.1M HEPES pH 6.6, 3.1M NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97627 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Aug 11, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97627 Å / Relative weight: 1
ReflectionResolution: 1.855→68.253 Å / Num. obs: 32643 / % possible obs: 95.7 % / Redundancy: 12.4 % / CC1/2: 0.999 / Rmerge(I) obs: 0.132 / Rpim(I) all: 0.04 / Rrim(I) all: 0.138 / Net I/σ(I): 13.1
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
1.855-1.96611.62.1781894516340.5380.6622.2781.459.4
5.465-68.2539.70.0631580416310.9990.020.06731.499.8

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Phasing

PhasingMethod: molecular replacement

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Processing

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

3brb


Resolution: 1.855→68.25 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.94 / SU B: 3.283 / SU ML: 0.093 / SU R Cruickshank DPI: 0.1264 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.126 / ESU R Free: 0.122 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: REFMAC5
RfactorNum. reflection% reflectionSelection details
Rfree0.219 1622 5 %RANDOM
Rwork0.1876 ---
obs0.1892 31020 86.62 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 105.85 Å2 / Biso mean: 39.466 Å2 / Biso min: 18.5 Å2
Baniso -1Baniso -2Baniso -3
1-0.04 Å2-0 Å2-0 Å2
2--0.04 Å2-0 Å2
3----0.08 Å2
Refinement stepCycle: final / Resolution: 1.855→68.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2273 0 57 132 2462
Biso mean--33.05 44.47 -
Num. residues----290
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0192383
X-RAY DIFFRACTIONr_bond_other_d0.0020.022280
X-RAY DIFFRACTIONr_angle_refined_deg1.4651.9693226
X-RAY DIFFRACTIONr_angle_other_deg0.97135239
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.775291
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.19723.36895
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.4715411
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.5061515
X-RAY DIFFRACTIONr_chiral_restr0.0890.2360
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022625
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02515
LS refinement shellResolution: 1.855→1.897 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.317 14 -
Rwork0.361 199 -
obs--7.78 %

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