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

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Basic information

Entry
Database: PDB / ID: 7olv
TitleMerTK kinase domain with type 1.5 inhibitor containing a di-methyl, cyano 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 / 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-VK2 / Tyrosine-protein kinase Mer
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.13 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 / pdbx_database_proc / Item: _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Oct 6, 2021Group: Data collection / Database references / Category: citation / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)35,0407
Polymers34,3821
Non-polymers6586
Water55831
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area760 Å2
ΔGint-37 kcal/mol
Surface area13930 Å2
MethodPISA
Unit cell
Length a, b, c (Å)91.379, 92.541, 71.387
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-VK2 / 4-[4-[5-[imidazo[1,2-a]pyridin-6-ylmethyl(methyl)amino]-1,3,4-oxadiazol-2-yl]-3-methyl-phenyl]-2,5-dimethyl-pyrazole-3-carbonitrile


Mass: 438.484 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H22N8O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-CL / CHLORIDE ION


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


Mass: 18.015 Da / Num. of mol.: 31 / 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: 2.19 Å3/Da / Density % sol: 43.96 %
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: SOLEIL / Beamline: PROXIMA 2 / Wavelength: 0.980073 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Aug 31, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.980073 Å / Relative weight: 1
ReflectionResolution: 2.13→65.02 Å / Num. obs: 11729 / % possible obs: 92.3 % / Redundancy: 6.1 % / CC1/2: 0.999 / Rmerge(I) obs: 0.054 / Rpim(I) all: 0.023 / Rrim(I) all: 0.059 / Net I/σ(I): 15.8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.146-2.3373.30.655860.6770.4050.7756.6
6.821-48.075.90.02358510.010.02599.3

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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: 2.13→65.02 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.935 / SU B: 9.046 / SU ML: 0.216 / SU R Cruickshank DPI: 0.5001 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.5 / ESU R Free: 0.271 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2473 586 5 %RANDOM
Rwork0.2078 ---
obs0.2099 11156 67.98 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 125.65 Å2 / Biso mean: 61.622 Å2 / Biso min: 32.67 Å2
Baniso -1Baniso -2Baniso -3
1-0.63 Å20 Å2-0 Å2
2--0.04 Å20 Å2
3----0.67 Å2
Refinement stepCycle: final / Resolution: 2.13→65.02 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2137 0 41 31 2209
Biso mean--54.79 49.61 -
Num. residues----273
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0192221
X-RAY DIFFRACTIONr_bond_other_d0.0020.022111
X-RAY DIFFRACTIONr_angle_refined_deg1.1451.973010
X-RAY DIFFRACTIONr_angle_other_deg0.87134841
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3895270
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.12823.47892
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.85415380
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.0281515
X-RAY DIFFRACTIONr_chiral_restr0.0610.2337
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0212455
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02492
LS refinement shellResolution: 2.132→2.187 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.349 6 -
Rwork0.336 62 -
obs--5.36 %

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