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- PDB-7avy: MerTK kinase domain in complex with quinazoline-based inhbitor -

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Basic information

Entry
Database: PDB / ID: 7avy
TitleMerTK kinase domain in complex with quinazoline-based inhbitor
ComponentsTyrosine-protein kinase Mer
KeywordsSIGNALING PROTEIN / tyrosine kinase / inhibitor / type1.5 kinase inhibitor / structure-based drug design / oncology
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 / 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 / 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-S4E / Tyrosine-protein kinase Mer
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.31 Å
AuthorsSchimpl, M. / Nissink, J.W.M. / Blackett, C. / Goldberg, K. / Hennessy, E.J. / Hardaker, E. / McCoull, W. / McMurray, L. / Collingwood, O. / Overman, R. ...Schimpl, M. / Nissink, J.W.M. / Blackett, C. / Goldberg, K. / Hennessy, E.J. / Hardaker, E. / McCoull, W. / McMurray, L. / Collingwood, O. / Overman, R. / Pflug, A. / Preston, M. / Rawlins, P. / Rivers, E. / Smith, P. / Underwood, E. / Truman, C. / Warwicker, J. / Winter, J. / Woodcock, S.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Generating Selective Leads for Mer Kinase Inhibitors-Example of a Comprehensive Lead-Generation Strategy.
Authors: Nissink, J.W.M. / Bazzaz, S. / Blackett, C. / Clark, M.A. / Collingwood, O. / Disch, J.S. / Gikunju, D. / Goldberg, K. / Guilinger, J.P. / Hardaker, E. / Hennessy, E.J. / Jetson, R. / Keefe, ...Authors: Nissink, J.W.M. / Bazzaz, S. / Blackett, C. / Clark, M.A. / Collingwood, O. / Disch, J.S. / Gikunju, D. / Goldberg, K. / Guilinger, J.P. / Hardaker, E. / Hennessy, E.J. / Jetson, R. / Keefe, A.D. / McCoull, W. / McMurray, L. / Olszewski, A. / Overman, R. / Pflug, A. / Preston, M. / Rawlins, P.B. / Rivers, E. / Schimpl, M. / Smith, P. / Truman, C. / Underwood, E. / Warwicker, J. / Winter-Holt, J. / Woodcock, S. / Zhang, Y.
History
DepositionNov 6, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 3, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 24, 2021Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Apr 7, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3May 1, 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

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase Mer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,7395
Polymers34,0001
Non-polymers7394
Water21612
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
  • monomer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Methodgel filtration
Unit cell
Length a, b, c (Å)68.890, 68.890, 177.580
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number151
Space group name H-MP3112

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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: kinase domain (571-864)
Source method: isolated from a genetically manipulated source
Details: Co-expressed with PTP1b / 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-S4E / N-(2-(2-cyclopropylethoxy)pyrimidin-5-yl)-7-methoxy-6-(piperidin-4-ylmethoxy)quinazolin-4-amine / ~{N}-[2-(2-cyclopropylethoxy)pyrimidin-5-yl]-7-methoxy-6-(piperidin-4-ylmethoxy)quinazolin-4-amine


Mass: 450.533 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H30N6O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 12 / 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: 3.58 Å3/Da / Density % sol: 65.62 % / Mosaicity: 0 °
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.5
Details: co-crystallisation of 0.3 mM protein with 0.5 mM compound (1 % DMSO) in 1.8 M lithium sulfate, 0.1 M PCTP pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.92819 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Jun 24, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92819 Å / Relative weight: 1
ReflectionResolution: 2.31→177.58 Å / Num. obs: 21601 / % possible obs: 100 % / Redundancy: 9.6 % / Biso Wilson estimate: 70.33 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.047 / Rpim(I) all: 0.016 / Rrim(I) all: 0.05 / Net I/σ(I): 16.8 / Num. measured all: 206918 / Scaling rejects: 63
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
2.31-2.378.31.5511301215750.6610.5751.6561.3100
10.33-177.588.40.03224022870.9990.0120.03557.399.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
Aimless0.5.26data scaling
PHASERphasing
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
DIALSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal model

Resolution: 2.31→59.66 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.94 / SU R Cruickshank DPI: 0.218 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.212 / SU Rfree Blow DPI: 0.179 / SU Rfree Cruickshank DPI: 0.183
RfactorNum. reflection% reflectionSelection details
Rfree0.249 1121 5.29 %RANDOM
Rwork0.228 ---
obs0.23 21186 98.3 %-
Displacement parametersBiso max: 189.48 Å2 / Biso mean: 99.07 Å2 / Biso min: 49.88 Å2
Baniso -1Baniso -2Baniso -3
1--3.5474 Å20 Å20 Å2
2---3.5474 Å20 Å2
3---7.0948 Å2
Refine analyzeLuzzati coordinate error obs: 0.42 Å
Refinement stepCycle: final / Resolution: 2.31→59.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2088 0 48 12 2148
Biso mean--82.38 78.44 -
Num. residues----270
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d751SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes354HARMONIC5
X-RAY DIFFRACTIONt_it2180HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion278SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2333SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2180HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg2959HARMONIC21.07
X-RAY DIFFRACTIONt_omega_torsion2.63
X-RAY DIFFRACTIONt_other_torsion19.18
LS refinement shellResolution: 2.31→2.33 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.4091 24 5.66 %
Rwork0.3453 400 -
all0.3491 424 -
obs--94.96 %
Refinement TLS params.Method: refined / Origin x: -17.3702 Å / Origin y: -1.3541 Å / Origin z: -16.6028 Å
111213212223313233
T-0.4135 Å2-0.3953 Å20.0714 Å2--0.7439 Å2-0.0348 Å2---0.8635 Å2
L1.8195 °20.7748 °20.4393 °2-2.4012 °20.798 °2--7.1098 °2
S-0.2663 Å °0.1569 Å °0.1877 Å °-0.5521 Å °0.5304 Å °0.3693 Å °-0.7982 Å °0.3445 Å °-0.2641 Å °
Refinement TLS groupSelection details: { A|* }

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