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- PDB-7cqe: Crystal structure of the catalytic domain of the proto-oncogene t... -

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Basic information

Entry
Database: PDB / ID: 7cqe
TitleCrystal structure of the catalytic domain of the proto-oncogene tyrosine-protein kinase MER in complex with AZD-7762
ComponentsTyrosine-protein kinase Mer
KeywordsTRANSFERASE / TRANSFERASE 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-YDJ / Tyrosine-protein kinase Mer
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.69 Å
AuthorsPark, T.H. / Lee, B.I.
Funding supportKorea, Democratic People's Republic Of, 1items
OrganizationGrant numberCountry
National Research Foundation (NRF, Korea)NRF-2019R1A2C1002545Korea, Democratic People's Republic Of
CitationJournal: Int J Mol Sci / Year: 2020
Title: Crystal Structure of the Kinase Domain of MerTK in Complex with AZD7762 Provides Clues for Structure-Based Drug Development.
Authors: Park, T.H. / Bae, S.H. / Bong, S.M. / Ryu, S.E. / Jang, H. / Lee, B.I.
History
DepositionAug 10, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 4, 2020Provider: repository / Type: Initial release
Revision 1.1Nov 11, 2020Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title ..._citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Nov 29, 2023Group: 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 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)68,65010
Polymers67,7122
Non-polymers9388
Water36020
1
A: Tyrosine-protein kinase Mer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3967
Polymers33,8561
Non-polymers5406
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area650 Å2
ΔGint-46 kcal/mol
Surface area13190 Å2
MethodPISA
2
C: Tyrosine-protein kinase Mer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,2543
Polymers33,8561
Non-polymers3982
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area140 Å2
ΔGint-11 kcal/mol
Surface area12150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)116.118, 69.203, 92.606
Angle α, β, γ (deg.)90.000, 118.420, 90.000
Int Tables number5
Space group name H-MC121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21C

NCS domain segments:

Component-ID: 0 / Ens-ID: 1 / Beg auth comp-ID: GLU / Beg label comp-ID: GLU / End auth comp-ID: LEU / End label comp-ID: LEU / Refine code: 0 / Auth seq-ID: 578 - 861 / Label seq-ID: 8 - 291

Dom-IDAuth asym-IDLabel asym-ID
1AA
2CB

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Components

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


Mass: 33856.230 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 BL21(DE3) (bacteria)
References: UniProt: Q12866, receptor protein-tyrosine kinase
#2: Chemical
ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-YDJ / 5-(3-fluorophenyl)-N-[(3S)-3-piperidyl]-3-ureido-thiophene-2-carboxamide


Mass: 362.422 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H19FN4O2S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 20 / 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: 2.42 Å3/Da / Density % sol: 49.19 %
Crystal growTemperature: 287 K / Method: vapor diffusion
Details: Protein 40mg/mL in 20mM Tris-Cl, pH 8.0, 500mM sodium chloride, 2mM DTT. inhibitor (5 mM final concentration) overnight, Mixed 1:1 with crystallization solution (100mM Tris-Cl, pH 8.5, 4M sodium chloride)

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PAL/PLS / Beamline: 11C / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 17, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.687→50 Å / Num. obs: 17283 / % possible obs: 95.9 % / Redundancy: 4.7 % / CC1/2: 0.986 / CC star: 0.997 / Rmerge(I) obs: 0.103 / Rpim(I) all: 0.051 / Rrim(I) all: 0.115 / Net I/σ(I): 13.8
Reflection shellResolution: 2.7→2.75 Å / Redundancy: 4 % / Rmerge(I) obs: 0.4 / Mean I/σ(I) obs: 3.333 / Num. unique obs: 738 / CC1/2: 0.875 / CC star: 0.966 / Rpim(I) all: 0.21 / Rrim(I) all: 0.455 / % possible all: 84.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4MH7

4mh7


Resolution: 2.69→43.53 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.87 / SU B: 12.897 / SU ML: 0.264 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.39 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2593 1652 10.1 %RANDOM
Rwork0.1968 ---
obs0.2031 14760 90.23 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 117.6 Å2 / Biso mean: 38.415 Å2 / Biso min: 2.59 Å2
Baniso -1Baniso -2Baniso -3
1-0.01 Å20 Å2-0 Å2
2---0.06 Å2-0 Å2
3---0.03 Å2
Refinement stepCycle: final / Resolution: 2.69→43.53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3948 0 56 20 4024
Biso mean--37.25 22.65 -
Num. residues----492
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0134081
X-RAY DIFFRACTIONr_bond_other_d0.0020.0173901
X-RAY DIFFRACTIONr_angle_refined_deg1.661.6555511
X-RAY DIFFRACTIONr_angle_other_deg1.2641.5979036
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.985482
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.03722.06199
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.12315739
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.8961525
X-RAY DIFFRACTIONr_chiral_restr0.0690.2516
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.024397
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02840
Refine LS restraints NCS

Ens-ID: 1 / Number: 7544 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.08 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2C
LS refinement shellResolution: 2.69→2.756 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.376 78 -
Rwork0.266 655 -
obs--54.82 %

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