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- PDB-6mep: Crystal structure of the catalytic domain of the proto-oncogene t... -

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Basic information

Entry
Database: PDB / ID: 6mep
TitleCrystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with inhibitor UNC3437
ComponentsTyrosine-protein kinase Mer
KeywordsTransferase/Transferase Inhibitor / Macrocyclic / Drug Design / Fibrinolytic Agents / Humans / Models / Molecular / Protein Kinase Inhibitors / Proto-Oncogene Proteins / Pyrimidines / Receptor Protein-Tyrosine Kinases / Structure-Activity Relationship / Thrombosis / Transferase-Transferase Inhibitor complex
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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-9VS / Tyrosine-protein kinase Mer
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.893 Å
AuthorsDa, C. / Zhang, D. / Stashko, M.A. / Cheng, A. / Hunter, D. / Norris-Drouin, J. / Graves, L. / Machius, M. / Miley, M.J. / DeRyckere, D. ...Da, C. / Zhang, D. / Stashko, M.A. / Cheng, A. / Hunter, D. / Norris-Drouin, J. / Graves, L. / Machius, M. / Miley, M.J. / DeRyckere, D. / Earp, H.S. / Graham, D.K. / Frye, S.V. / Wang, X. / Kireev, D.
CitationJournal: J.Am.Chem.Soc. / Year: 2019
Title: Data-Driven Construction of Antitumor Agents with Controlled Polypharmacology.
Authors: Da, C. / Zhang, D. / Stashko, M. / Vasileiadi, E. / Parker, R.E. / Minson, K.A. / Huey, M.G. / Huelse, J.M. / Hunter, D. / Gilbert, T.S.K. / Norris-Drouin, J. / Miley, M. / Herring, L.E. / ...Authors: Da, C. / Zhang, D. / Stashko, M. / Vasileiadi, E. / Parker, R.E. / Minson, K.A. / Huey, M.G. / Huelse, J.M. / Hunter, D. / Gilbert, T.S.K. / Norris-Drouin, J. / Miley, M. / Herring, L.E. / Graves, L.M. / DeRyckere, D. / Earp, H.S. / Graham, D.K. / Frye, S.V. / Wang, X. / Kireev, D.
History
DepositionSep 6, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 11, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 9, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Oct 16, 2019Group: Data collection / 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 1.3Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase Mer
B: Tyrosine-protein kinase Mer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)73,27210
Polymers71,7792
Non-polymers1,4938
Water543
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2760 Å2
ΔGint-71 kcal/mol
Surface area23620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)51.366, 92.048, 69.690
Angle α, β, γ (deg.)90.000, 101.670, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Tyrosine-protein kinase Mer / Proto-oncogene c-Mer / Receptor tyrosine kinase MerTK


Mass: 35889.434 Da / Num. of mol.: 2 / Fragment: catalytic domain
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-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-9VS / cis-4-[(2-[(4-{[4-(1,3-dioxolan-2-yl)pyridin-2-yl]ethynyl}phenyl)amino]-5-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}pyrimidin-4-yl)amino]cyclohexan-1-ol


Mass: 645.793 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C38H43N7O3
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: H2O

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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: 45.28 % / Mosaicity: 0.647 ° / Mosaicity esd: 0.016 °
Crystal growTemperature: 285.2 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: Protein at 32.5 mg/mL (in 20 mM Tris pH 8.0, 500 mM NaCl, 2mM BME) was incubated overnight with inhibitor at 2.5 mM final concentration, and then was mixed 1:1 with crystallization solution ...Details: Protein at 32.5 mg/mL (in 20 mM Tris pH 8.0, 500 mM NaCl, 2mM BME) was incubated overnight with inhibitor at 2.5 mM final concentration, and then was mixed 1:1 with crystallization solution (27-33% (v/v) Peg 400, 200 mM MgCl2, 100 mM Tris pH 8.5).

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1.0743 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Oct 19, 2013
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0743 Å / Relative weight: 1
ReflectionResolution: 2.893→50 Å / Num. obs: 14260 / % possible obs: 99.9 % / Redundancy: 4.2 % / Biso Wilson estimate: 43.48 Å2 / Rmerge(I) obs: 0.142 / Χ2: 0.956 / Net I/σ(I): 5.7
Reflection shellResolution: 2.893→2.92 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.771 / Num. unique obs: 337 / Χ2: 0.968 / % possible all: 98.5

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
PHENIX1.10.1_2155refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.893→37.069 Å / SU ML: 0.35 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 28.92
RfactorNum. reflection% reflection
Rfree0.2682 1000 7.92 %
Rwork0.2048 --
obs0.2099 12634 88.53 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 156.46 Å2 / Biso mean: 42.3848 Å2 / Biso min: 6.51 Å2
Refinement stepCycle: final / Resolution: 2.893→37.069 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3904 0 186 3 4093
Biso mean--60.46 12.14 -
Num. residues----486
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0024094
X-RAY DIFFRACTIONf_angle_d0.6435532
X-RAY DIFFRACTIONf_chiral_restr0.04611
X-RAY DIFFRACTIONf_plane_restr0.002685
X-RAY DIFFRACTIONf_dihedral_angle_d13.6192469
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 7

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.8934-3.04590.2592880.20361026111455
3.0459-3.23660.28761180.23111373149174
3.2366-3.48640.29431460.21441701184791
3.4864-3.83690.27571600.192618552015100
3.8369-4.39130.21991620.182218902052100
4.3913-5.52970.24521610.218722033100
5.5297-37.07210.31161650.22419172082100

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