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- PDB-7avz: MerTK kinase domain in complex with a bisaminopyrimidine inhibitor -

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Basic information

Entry
Database: PDB / ID: 7avz
TitleMerTK kinase domain in complex with a bisaminopyrimidine inhibitor
ComponentsTyrosine-protein kinase Mer
KeywordsSIGNALING PROTEIN / tyrosine kinase / inhibitor / type3 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 / positive regulation of phagocytosis / 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 / positive regulation of phagocytosis / phagocytosis / transmembrane receptor protein tyrosine kinase activity / substrate adhesion-dependent cell spreading / phosphatidylinositol 3-kinase/protein kinase B signal transduction / establishment of localization in cell / Cell surface interactions at the vascular wall / receptor protein-tyrosine kinase / platelet activation / cell surface receptor protein tyrosine kinase signaling pathway / cell migration / retina development in camera-type eye / cell-cell signaling / nervous system development / spermatogenesis / 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-S4N / Tyrosine-protein kinase Mer
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.04 Å
AuthorsPflug, A. / Nissink, J.W.M. / Blackett, C. / Goldberg, K. / Hennessy, E.J. / Hardaker, E. / McCoull, W. / McMurray, L. / Collingwood, O. / Overman, R. ...Pflug, A. / Nissink, J.W.M. / Blackett, C. / Goldberg, K. / Hennessy, E.J. / Hardaker, E. / McCoull, W. / McMurray, L. / Collingwood, O. / Overman, R. / Preston, M. / Rawlins, P. / Rivers, E. / Schimpl, M. / 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

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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)34,8562
Polymers34,3821
Non-polymers4751
Water1,20767
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)92.640, 93.320, 71.690
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-1028-

HOH

21A-1063-

HOH

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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-S4N / (R)-N2-(4-(cyclopropylmethoxy)-3,5-difluorophenyl)-5-(3-methylpiperazin-1-yl)-N4-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4-diamine / ~{N}2-[4-(cyclopropylmethoxy)-3,5-bis(fluoranyl)phenyl]-5-[(3~{R})-3-methylpiperazin-1-yl]-~{N}4-(oxan-4-yl)pyrimidine-2,4-diamine


Mass: 474.547 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H32F2N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 67 / 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: 2.25 Å3/Da / Density % sol: 45.41 % / Mosaicity: 0 °
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: 16 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 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 10, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.04→46.66 Å / Num. obs: 20121 / % possible obs: 99.8 % / Redundancy: 6.5 % / Biso Wilson estimate: 47.51 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.044 / Rpim(I) all: 0.019 / Rrim(I) all: 0.048 / Net I/σ(I): 23.4 / Num. measured all: 131696
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
2.04-2.096.71.222983914590.6760.5051.3241.699.9
9.12-46.665.30.015140426310.0070.01695.498.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimless0.5.27data scaling
PHASERphasing
BUSTER2.11.7refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal model

Resolution: 2.04→20.96 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.937 / SU R Cruickshank DPI: 0.186 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.187 / SU Rfree Blow DPI: 0.154 / SU Rfree Cruickshank DPI: 0.154
RfactorNum. reflection% reflectionSelection details
Rfree0.229 1085 5.4 %RANDOM
Rwork0.206 ---
obs0.207 20081 99.8 %-
Displacement parametersBiso max: 123.93 Å2 / Biso mean: 60.3 Å2 / Biso min: 26.53 Å2
Baniso -1Baniso -2Baniso -3
1-4.8528 Å20 Å20 Å2
2---12.6347 Å20 Å2
3---7.7819 Å2
Refine analyzeLuzzati coordinate error obs: 0.32 Å
Refinement stepCycle: final / Resolution: 2.04→20.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2113 0 34 67 2214
Biso mean--54.5 54.45 -
Num. residues----268
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d777SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes358HARMONIC5
X-RAY DIFFRACTIONt_it2193HARMONIC20
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_contact2559SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2193HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg2969HARMONIC20.93
X-RAY DIFFRACTIONt_omega_torsion2.42
X-RAY DIFFRACTIONt_other_torsion19.82
LS refinement shellResolution: 2.04→2.05 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.3209 26 6.47 %
Rwork0.2285 376 -
all0.234 402 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: 14.8423 Å / Origin y: 28.6858 Å / Origin z: -7.8112 Å
111213212223313233
T0.0051 Å20.009 Å20.016 Å2-0.1169 Å2-0.0345 Å2---0.064 Å2
L3.2595 °20.7836 °20.9517 °2-1.1444 °20.2488 °2--1.4446 °2
S0.0703 Å °-0.131 Å °0.0167 Å °0.063 Å °0.0699 Å °-0.0512 Å °-0.1645 Å °-0.1446 Å °-0.1402 Å °
Refinement TLS groupSelection details: { A|* }

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