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- PDB-7aw1: MerTK kinase domain in complex with a type 2 inhibitor -

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Basic information

Entry
Database: PDB / ID: 7aw1
TitleMerTK kinase domain in complex with a type 2 inhibitor
ComponentsTyrosine-protein kinase Mer
KeywordsSIGNALING PROTEIN / tyrosine kinase / inhibitor / type2 kinase inhibitor / structure-based drug design / high-throughput screening / 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 / 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. / Immunoglobulin subtype / Immunoglobulin / Tyrosine-protein kinase, active site / 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-S4T / Tyrosine-protein kinase Mer
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.98 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: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_atoms
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)34,9742
Polymers34,3821
Non-polymers5931
Water1,44180
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)93.450, 94.740, 72.410
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221

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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 (571-864) / Mutation: K591R,K693R,K702R,K856R
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-S4T / N-(6-(4-(3-(4-((5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)phenoxy)pyrimidin-4-yl)cyclopropanecarboxamide / ~{N}-[6-[4-[[4-(6,8-dihydro-5~{H}-imidazo[1,2-a]pyrazin-7-ylmethyl)-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]pyrimidin-4-yl]cyclopropanecarboxamide


Mass: 592.572 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H27F3N8O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 80 / 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: 2.33 Å3/Da / Density % sol: 47.23 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 8.5
Details: 4.0-4.5 M sodium chloride, 0.1 M Tris pH 8.5: 32 h soak with 20 % DMSO and 20 mM compound

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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: Sep 16, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92819 Å / Relative weight: 1
ReflectionResolution: 1.977→66.53 Å / Num. obs: 22860 / % possible obs: 100 % / Redundancy: 6.5 % / Biso Wilson estimate: 48.02 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.035 / Rpim(I) all: 0.015 / Rrim(I) all: 0.038 / Net I/σ(I): 23.5 / Num. measured all: 148664
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
1.977-2.0116.40.817725811330.8490.350.892.499.1
5.365-66.535.70.0217093124110.0090.02355.699.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimlessdata scaling
PHASERphasing
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal model

Resolution: 1.98→48.99 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.944 / SU R Cruickshank DPI: 0.159 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.161 / SU Rfree Blow DPI: 0.139 / SU Rfree Cruickshank DPI: 0.138
RfactorNum. reflection% reflectionSelection details
Rfree0.225 1147 5.02 %RANDOM
Rwork0.202 ---
obs0.203 22842 99.9 %-
Displacement parametersBiso max: 159.21 Å2 / Biso mean: 61.47 Å2 / Biso min: 25.33 Å2
Baniso -1Baniso -2Baniso -3
1-3.5217 Å20 Å20 Å2
2---9.0408 Å20 Å2
3---5.5191 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: final / Resolution: 1.98→48.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2106 0 34 80 2220
Biso mean--67.22 59.63 -
Num. residues----268
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d767SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes360HARMONIC5
X-RAY DIFFRACTIONt_it2187HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion279SEMIHARMONIC5
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_contact2353SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2197HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg2979HARMONIC20.95
X-RAY DIFFRACTIONt_omega_torsion2.48
X-RAY DIFFRACTIONt_other_torsion17.97
LS refinement shellResolution: 1.98→1.99 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2914 23 5.03 %
Rwork0.2277 434 -
all0.2307 457 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: 14.8423 Å / Origin y: 28.6858 Å / Origin z: -7.8112 Å
111213212223313233
T-0.198 Å2-0.0134 Å20.0198 Å2--0.1852 Å2-0.0543 Å2---0.2676 Å2
L3.5409 °20.6735 °20.2612 °2-0.983 °20.1376 °2--1.8227 °2
S0.2033 Å °-0.1849 Å °0.2114 Å °0.1114 Å °0.0364 Å °0.0433 Å °-0.1848 Å °0.0052 Å °-0.2397 Å °
Refinement TLS groupSelection details: { A|* }

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