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- PDB-7aw2: MerTK kinase domain with type 1.5 inhibitor from a DNA-encoded library -

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Basic information

Entry
Database: PDB / ID: 7aw2
TitleMerTK kinase domain with type 1.5 inhibitor from a DNA-encoded library
ComponentsTyrosine-protein kinase Mer
KeywordsSIGNALING PROTEIN / tyrosine kinase / inhibitor / type1.5 kinase inhibitor / structure-based drug design / DNA-encoded library / 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. / 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-S4W / Tyrosine-protein kinase Mer
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.1 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)34,7982
Polymers34,3821
Non-polymers4161
Water1,24369
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)92.280, 94.350, 71.370
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-S4W / 5-(2'-chloro-[1,1'-biphenyl]-4-yl)-N-(imidazo[1,2-a]pyridin-6-ylmethyl)-N-methyl-1,3,4-oxadiazol-2-amine / 5-[4-(2-chlorophenyl)phenyl]-~{N}-(imidazo[1,2-a]pyridin-6-ylmethyl)-~{N}-methyl-1,3,4-oxadiazol-2-amine


Mass: 415.875 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H18ClN5O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 69 / 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: 45.56 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 8.5
Details: 0.5 mM protein was crystallised in 4.3 M sodium chloride, 0.1 M Tris pH 8.5 and soaked for 24 h with 20 mM compound and 20 % DMSO

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 2 / Wavelength: 0.9801 Å
DetectorType: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: Nov 23, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9801 Å / Relative weight: 1
ReflectionResolution: 2.1→48.44 Å / Num. obs: 18583 / % possible obs: 99.7 % / Redundancy: 6.7 % / Biso Wilson estimate: 57.22 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.059 / Rpim(I) all: 0.025 / Rrim(I) all: 0.064 / Net I/σ(I): 15.8 / Num. measured all: 124104
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
2.1-2.156.61.237874013210.7370.5141.3431.496.2
9.38-48.445.70.02513862430.9990.0110.02752.299.1

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimless0.5.17data scaling
PHASERphasing
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal model

Resolution: 2.1→20.73 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.937 / SU R Cruickshank DPI: 0.206 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.209 / SU Rfree Blow DPI: 0.171 / SU Rfree Cruickshank DPI: 0.172
RfactorNum. reflection% reflectionSelection details
Rfree0.238 927 5 %RANDOM
Rwork0.207 ---
obs0.208 18540 99.7 %-
Displacement parametersBiso max: 139.65 Å2 / Biso mean: 65.54 Å2 / Biso min: 29.82 Å2
Baniso -1Baniso -2Baniso -3
1-8.3684 Å20 Å20 Å2
2---14.7505 Å20 Å2
3---6.3821 Å2
Refine analyzeLuzzati coordinate error obs: 0.31 Å
Refinement stepCycle: final / Resolution: 2.1→20.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2103 0 30 69 2202
Biso mean--55.12 57.34 -
Num. residues----270
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d740SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes358HARMONIC5
X-RAY DIFFRACTIONt_it2179HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion280SEMIHARMONIC5
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_contact2552SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2179HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg2952HARMONIC21.02
X-RAY DIFFRACTIONt_omega_torsion2.87
X-RAY DIFFRACTIONt_other_torsion18.67
LS refinement shellResolution: 2.1→2.11 Å / Rfactor Rfree error: 0 / Total num. of bins used: 46
RfactorNum. reflection% reflection
Rfree0.3584 20 4.95 %
Rwork0.2968 384 -
all0.2996 404 -
obs--88.38 %
Refinement TLS params.Method: refined / Origin x: 15.2423 Å / Origin y: 29.0035 Å / Origin z: -7.6245 Å
111213212223313233
T-0.0845 Å20.0284 Å2-0.0028 Å2--0.0852 Å2-0.0381 Å2---0.074 Å2
L3.2491 °20.8554 °20.8293 °2-1.1612 °20.3636 °2--2.4865 °2
S0.1449 Å °-0.0804 Å °0.0297 Å °0.0771 Å °0.0775 Å °-0.0459 Å °-0.1383 Å °-0.053 Å °-0.2224 Å °
Refinement TLS groupSelection details: { A|* }

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