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- PDB-7ols: MerTK kinase domain with type 1.5 inhibitor containing a di-methy... -

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Basic information

Entry
Database: PDB / ID: 7ols
TitleMerTK kinase domain with type 1.5 inhibitor containing a di-methyl pyrazole group
ComponentsTyrosine-protein kinase Mer
KeywordsTRANSFERASE / tyrosine kinase inhibitor / structure-based drug design / type 1.5 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 / 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-VJZ / Tyrosine-protein kinase Mer
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.89 Å
AuthorsPflug, A. / Schimpl, M. / McCoull, W. / Nissink, J.W.M. / Winter-Holt, J.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Optimization of an Imidazo[1,2- a ]pyridine Series to Afford Highly Selective Type I1/2 Dual Mer/Axl Kinase Inhibitors with In Vivo Efficacy.
Authors: McCoull, W. / Boyd, S. / Brown, M.R. / Coen, M. / Collingwood, O. / Davies, N.L. / Doherty, A. / Fairley, G. / Goldberg, K. / Hardaker, E. / He, G. / Hennessy, E.J. / Hopcroft, P. / Hodgson, ...Authors: McCoull, W. / Boyd, S. / Brown, M.R. / Coen, M. / Collingwood, O. / Davies, N.L. / Doherty, A. / Fairley, G. / Goldberg, K. / Hardaker, E. / He, G. / Hennessy, E.J. / Hopcroft, P. / Hodgson, G. / Jackson, A. / Jiang, X. / Karmokar, A. / Laine, A.L. / Lindsay, N. / Mao, Y. / Markandu, R. / McMurray, L. / McLean, N. / Mooney, L. / Musgrove, H. / Nissink, J.W.M. / Pflug, A. / Reddy, V.P. / Rawlins, P.B. / Rivers, E. / Schimpl, M. / Smith, G.F. / Tentarelli, S. / Travers, J. / Troup, R.I. / Walton, J. / Wang, C. / Wilkinson, S. / Williamson, B. / Winter-Holt, J. / Yang, D. / Zheng, Y. / Zhu, Q. / Smith, P.D.
History
DepositionMay 20, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 15, 2021Provider: repository / Type: Initial release
Revision 1.1Sep 29, 2021Group: Data collection / Database references / Category: citation / diffrn_source / pdbx_database_proc
Item: _citation.pdbx_database_id_PubMed / _citation.title / _diffrn_source.pdbx_synchrotron_site
Revision 1.2Oct 6, 2021Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / diffrn_source / pdbx_initial_refinement_model
Item: _diffrn_source.pdbx_synchrotron_site

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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)35,0157
Polymers34,3821
Non-polymers6336
Water1,928107
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area750 Å2
ΔGint-36 kcal/mol
Surface area14230 Å2
MethodPISA
Unit cell
Length a, b, c (Å)92.710, 94.172, 71.627
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: kinase domain (571-864)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MERTK, MER / Production host: Escherichia coli (E. coli)
References: UniProt: Q12866, receptor protein-tyrosine kinase
#2: Chemical ChemComp-VJZ / 5-[4-(1,5-dimethylpyrazol-4-yl)-2-methyl-phenyl]-~{N}-(imidazo[1,2-a]pyridin-6-ylmethyl)-~{N}-methyl-1,3,4-oxadiazol-2-amine


Mass: 413.475 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H23N7O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-CL / CHLORIDE ION / Chloride


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


Mass: 18.015 Da / Num. of mol.: 107 / 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: 2.27 Å3/Da / Density % sol: 45.9 %
Crystal growTemperature: 293 K / Method: vapor diffusion / Details: 0.1 M Tris pH 8.5, 4.3 M NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97625 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 7, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.89→66.07 Å / Num. obs: 16521 / % possible obs: 94.6 % / Redundancy: 6.4 % / CC1/2: 0.999 / Rmerge(I) obs: 0.071 / Rpim(I) all: 0.031 / Rrim(I) all: 0.078 / Net I/σ(I): 15.3
Reflection shell

Diffraction-ID: 1 / Redundancy: 5.9 %

Resolution (Å)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.895-2.0271.23448388270.5520.5541.3561.467.6
6.109-66.0670.03348328250.9990.0140.03641.299.4

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Processing

Software
NameVersionClassification
autoPROCdata reduction
Aimlessdata scaling
REFMAC5.8.0135refinement
PDB_EXTRACT3.27data extraction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3BRB

3brb


Resolution: 1.89→66.07 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.891 / SU B: 5.526 / SU ML: 0.153 / SU R Cruickshank DPI: 0.2871 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.287 / ESU R Free: 0.239 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2819 805 4.9 %RANDOM
Rwork0.2187 ---
obs0.2215 15714 65.38 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 95.66 Å2 / Biso mean: 47.483 Å2 / Biso min: 23.89 Å2
Baniso -1Baniso -2Baniso -3
1-0.35 Å20 Å2-0 Å2
2---0.17 Å20 Å2
3----0.18 Å2
Refinement stepCycle: final / Resolution: 1.89→66.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2145 0 39 107 2291
Biso mean--45.22 48.23 -
Num. residues----273
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0192227
X-RAY DIFFRACTIONr_bond_other_d0.0010.022129
X-RAY DIFFRACTIONr_angle_refined_deg1.0511.973016
X-RAY DIFFRACTIONr_angle_other_deg0.86234878
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.9775270
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.90423.11893
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.55115384
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.8581517
X-RAY DIFFRACTIONr_chiral_restr0.060.2337
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.0212459
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02501
LS refinement shellResolution: 1.895→1.944 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.403 7 -
Rwork0.357 140 -
obs--7.92 %

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