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- PDB-7ab1: Crystal structure of MerTK kinase domain in complex with Gilteritinib -

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Basic information

Entry
Database: PDB / ID: 7ab1
TitleCrystal structure of MerTK kinase domain in complex with Gilteritinib
ComponentsTyrosine-protein kinase Mer
KeywordsTRANSFERASE / tyrosine kinase inhibitor / structure-based drug design / type 1 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 / cell surface receptor protein tyrosine kinase signaling pathway / Cell surface interactions at the vascular wall / establishment of localization in cell / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / platelet activation / cell migration / nervous system development / cell-cell signaling / retina development in camera-type eye / 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 / Phosphorylase Kinase; domain 1 / Ig-like domain profile. / Immunoglobulin-like domain / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Immunoglobulin-like domain superfamily / Transferase(Phosphotransferase); domain 1 / 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-C6F / Tyrosine-protein kinase Mer
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.93 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 1.0Oct 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)35,1547
Polymers34,3821
Non-polymers7736
Water97354
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area720 Å2
ΔGint-36 kcal/mol
Surface area14100 Å2
Unit cell
Length a, b, c (Å)93.302, 94.120, 70.734
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

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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: MERTK kinase domain / Mutation: K591R, K693R, K702R, K856R
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-C6F / 6-ethyl-3-[[3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]amino]-5-(oxan-4-ylamino)pyrazine-2-carboxamide / gilteritinib


Mass: 552.711 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H44N8O3 / Feature type: SUBJECT OF INVESTIGATION / Comment: anticancer*YM
#3: Chemical
ChemComp-CL / CHLORIDE ION


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


Mass: 18.015 Da / Num. of mol.: 54 / 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: 2.26 Å3/Da / Density % sol: 45.53 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 8.5 / Details: 0.1M Tris pH 8.5, 4.3M NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.976254 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jan 23, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976254 Å / Relative weight: 1
ReflectionResolution: 1.927→46.651 Å / Num. obs: 18953 / % possible obs: 88.3 % / Redundancy: 5.3 % / CC1/2: 0.996 / Rmerge(I) obs: 0.115 / Rpim(I) all: 0.05 / Rrim(I) all: 0.125 / Net I/σ(I): 9.8
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
1.927-2.0514.41.11641799490.8080.5941.2691.556.3
5.825-46.6516.20.12658789480.9940.0540.13718.899.9

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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: 1.93→46.651 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.913 / SU B: 6.854 / SU ML: 0.184 / SU R Cruickshank DPI: 0.2441 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.244 / ESU R Free: 0.222 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: BUSTER
RfactorNum. reflection% reflectionSelection details
Rfree0.2979 893 4.8 %RANDOM
Rwork0.2344 ---
obs0.2375 17788 78.14 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 121.17 Å2 / Biso mean: 52.816 Å2 / Biso min: 28.03 Å2
Baniso -1Baniso -2Baniso -3
1-0.31 Å20 Å20 Å2
2---0.69 Å2-0 Å2
3---0.38 Å2
Refinement stepCycle: final / Resolution: 1.93→46.651 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2075 0 48 54 2177
Biso mean--66.49 51.79 -
Num. residues----270
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0192166
X-RAY DIFFRACTIONr_bond_other_d0.0020.022042
X-RAY DIFFRACTIONr_angle_refined_deg1.5341.9672940
X-RAY DIFFRACTIONr_angle_other_deg0.97534675
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3055267
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.85623.48886
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.54915350
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.4671513
X-RAY DIFFRACTIONr_chiral_restr0.0840.2335
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022395
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02473
LS refinement shellResolution: 1.93→1.977 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.439 7 -
Rwork0.453 152 -
obs--9.06 %

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