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- PDB-7aw4: MerTK kinase domain with type 3 inhibitor from a DNA-encoded library -

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Basic information

Entry
Database: PDB / ID: 7aw4
TitleMerTK kinase domain with type 3 inhibitor from a DNA-encoded library
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 / 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-S5E / Tyrosine-protein kinase Mer
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.98 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
Revision 1.3May 1, 2024Group: 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)73,48713
Polymers71,7792
Non-polymers1,70811
Water5,062281
1
A: Tyrosine-protein kinase Mer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,8238
Polymers35,8891
Non-polymers9347
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Methodgel filtration
2
B: Tyrosine-protein kinase Mer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,6645
Polymers35,8891
Non-polymers7744
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Methodgel filtration
Unit cell
Length a, b, c (Å)50.568, 90.490, 69.415
Angle α, β, γ (deg.)90.000, 99.370, 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: kinase domain (571-864)
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-S5E / 3-methyl-5-(4-methyl-1,2,3-thiadiazol-5-yl)-N-((R)-1-(((R)-3-(methylamino)-3-oxo-1-(4-(trifluoromethyl)phenyl)propyl)amino)-1-oxo-4-phenylbutan-2-yl)isoxazole-4-carboxamide / 3-methyl-~{N}-[(2~{R})-1-[[(1~{R})-3-(methylamino)-3-oxidanylidene-1-[4-(trifluoromethyl)phenyl]propyl]amino]-1-oxidanylidene-4-phenyl-butan-2-yl]-5-(4-methyl-1,2,3-thiadiazol-5-yl)-1,2-oxazole-4-carboxamide


Mass: 614.639 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H29F3N6O4S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#4: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 281 / 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: 2.18 Å3/Da / Density % sol: 43.66 % / Mosaicity: 0 °
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 7.5
Details: 0.3 mM protein co-crystallised with 0.5 mM compound (1 % DMSO) in 25 % PEG3350, 0.2 M MgCl2, 0.1 M PCTP pH 7.5

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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: Jul 28, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.98→49.86 Å / Num. obs: 42994 / % possible obs: 99.9 % / Redundancy: 3.3 % / Biso Wilson estimate: 23.45 Å2 / CC1/2: 0.987 / Rmerge(I) obs: 0.154 / Rpim(I) all: 0.1 / Rrim(I) all: 0.184 / Net I/σ(I): 4.6 / Num. measured all: 141247 / Scaling rejects: 44
Reflection shell

Diffraction-ID: 1 / Redundancy: 3.2 %

Resolution (Å)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.98-2.031.2351025231850.5560.8041.4781.199.9
8.85-49.860.05616395110.9920.0360.06712.299.6

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
Aimless0.5.32data scaling
AMoREphasing
BUSTER2.11.7refinement
PDB_EXTRACT3.27data extraction
DIALSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal model

Resolution: 1.98→39.48 Å / Cor.coef. Fo:Fc: 0.921 / Cor.coef. Fo:Fc free: 0.896 / SU R Cruickshank DPI: 0.189 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.192 / SU Rfree Blow DPI: 0.163 / SU Rfree Cruickshank DPI: 0.163
RfactorNum. reflection% reflectionSelection details
Rfree0.246 2053 4.99 %RANDOM
Rwork0.214 ---
obs0.215 41173 95.5 %-
Displacement parametersBiso max: 127.17 Å2 / Biso mean: 36.83 Å2 / Biso min: 8.71 Å2
Baniso -1Baniso -2Baniso -3
1-1.8252 Å20 Å20.7892 Å2
2---0.4896 Å20 Å2
3----1.3356 Å2
Refine analyzeLuzzati coordinate error obs: 0.33 Å
Refinement stepCycle: final / Resolution: 1.98→39.48 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4114 0 113 281 4508
Biso mean--38.98 33.5 -
Num. residues----521
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1511SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes712HARMONIC5
X-RAY DIFFRACTIONt_it4327HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion546SEMIHARMONIC5
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_contact5073SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4327HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg5854HARMONIC20.93
X-RAY DIFFRACTIONt_omega_torsion2.42
X-RAY DIFFRACTIONt_other_torsion16.96
LS refinement shellResolution: 1.98→2 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.2563 33 4 %
Rwork0.2284 791 -
all0.2297 824 -
obs--69.22 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.1272-0.0671-0.19590.8770.12620.60980.0914-0.00140.00990.12540.03550.1114-0.2822-0.0703-0.12690.49520.06060.1177-0.15050.0316-0.1404-9.240.789226.7393
20.57680.10540.14621.35470.10861.3130.03240.1874-0.2389-0.29470.0933-0.02880.5280.0006-0.12570.506-0.03660.0063-0.255-0.0832-0.2004-5.6447-29.69546.0636
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A576 - 862
2X-RAY DIFFRACTION2{ B|* }B574 - 862

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