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- PDB-7aw3: MerTK kinase domain with type 1 inhibitor from a DNA-encoded library -

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Basic information

Entry
Database: PDB / ID: 7aw3
TitleMerTK kinase domain with type 1 inhibitor from a DNA-encoded library
ComponentsTyrosine-protein kinase Mer
KeywordsSIGNALING PROTEIN / tyrosine kinase / inhibitor / type1 kinase inhibitor / structure-based drug design / DNA encoded library / 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 / 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 / establishment of localization in cell / Cell surface interactions at the vascular wall / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / GPI-linked ephrin receptor activity / transmembrane-ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / platelet activation / cell surface receptor protein tyrosine kinase signaling pathway / cell migration / cell-cell signaling / nervous system development / retina development in camera-type eye / spermatogenesis / histone H3Y41 kinase activity / histone H2AXY142 kinase activity / 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 / Phosphorylase Kinase; domain 1 / Immunoglobulin-like domain superfamily / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-S4Z / Tyrosine-protein kinase Mer
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.99 Å
AuthorsSchimpl, M. / Nissink, J.W.M. / Blackett, C. / Goldberg, K. / Hennessy, E.J. / Hardaker, E. / McCoull, W. / McMurray, L. / Collingwood, O. / Overman, R. ...Schimpl, M. / Nissink, J.W.M. / Blackett, C. / Goldberg, K. / Hennessy, E.J. / Hardaker, E. / McCoull, W. / McMurray, L. / Collingwood, O. / Overman, R. / Pflug, A. / Preston, M. / Rawlins, P. / Rivers, E. / 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

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Assembly

Deposited unit
A: Tyrosine-protein kinase Mer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,8812
Polymers34,3821
Non-polymers4991
Water1,08160
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)91.600, 91.900, 71.660
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-1025-

HOH

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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) / Mutation: K591R,K693R,K702R,K856R
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-S4Z / 2-(1-((5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxamido)methyl)-2-azabicyclo[2.1.1]hexan-2-yl)-N-methyl-4-(trifluoromethyl)thiazole-5-carboxamide / 2-[1-[[(5-chloranyl-1~{H}-pyrrolo[2,3-b]pyridin-3-yl)carbonylamino]methyl]-2-azabicyclo[2.1.1]hexan-2-yl]-~{N}-methyl-4-(trifluoromethyl)-1,3-thiazole-5-carboxamide


Mass: 498.909 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H18ClF3N6O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 60 / 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: 43.92 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 8.5
Details: 0.5 mM protein was crystallised in 4.3 M sodium chloride, 0.1 M Tris pH 8.5 and crystal soaked for 24 h with 20 mM compound and 20 % DMSO

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 6, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.99→64.8 Å / Num. obs: 21058 / % possible obs: 99.9 % / Redundancy: 6.2 % / Biso Wilson estimate: 35.01 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.074 / Rpim(I) all: 0.032 / Rrim(I) all: 0.081 / Net I/σ(I): 10.4 / Num. measured all: 130879 / Scaling rejects: 97
Reflection shell

Diffraction-ID: 1 / % possible all: 99.9

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs
1.99-2.046.21.441940815230.7610.6261.5741.3
8.9-64.85.30.03214782770.9980.0150.03530.7

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
Aimless0.5.31data scaling
PHASERphasing
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
DIALSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal model

Resolution: 1.99→48.09 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.931 / SU R Cruickshank DPI: 0.183 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.183 / SU Rfree Blow DPI: 0.157 / SU Rfree Cruickshank DPI: 0.158
RfactorNum. reflection% reflectionSelection details
Rfree0.245 978 4.69 %RANDOM
Rwork0.216 ---
obs0.217 20862 98.8 %-
Displacement parametersBiso max: 126.57 Å2 / Biso mean: 51.15 Å2 / Biso min: 17.94 Å2
Baniso -1Baniso -2Baniso -3
1-6.2732 Å20 Å20 Å2
2---13.8623 Å20 Å2
3---7.5891 Å2
Refine analyzeLuzzati coordinate error obs: 0.32 Å
Refinement stepCycle: final / Resolution: 1.99→48.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2102 0 33 60 2195
Biso mean--47.14 45.4 -
Num. residues----269
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d759SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes359HARMONIC5
X-RAY DIFFRACTIONt_it2182HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion280SEMIHARMONIC5
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_contact2502SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2182HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg2964HARMONIC20.98
X-RAY DIFFRACTIONt_omega_torsion2.7
X-RAY DIFFRACTIONt_other_torsion21.57
LS refinement shellResolution: 1.99→2.01 Å / Rfactor Rfree error: 0 / Total num. of bins used: 48
RfactorNum. reflection% reflection
Rfree0.2799 23 5.29 %
Rwork0.3056 412 -
all0.3038 435 -
obs--86.97 %
Refinement TLS params.Method: refined / Origin x: 15.2423 Å / Origin y: 29.0035 Å / Origin z: -7.6245 Å
111213212223313233
T-0.3478 Å20.0045 Å2-0.0097 Å2--0.1841 Å2-0.0313 Å2---0.3983 Å2
L2.5358 °20.3856 °20.2291 °2-0.8796 °20.0187 °2--1.562 °2
S0.0892 Å °-0.1079 Å °0.122 Å °0.0892 Å °0.059 Å °0.0044 Å °-0.1587 Å °-0.071 Å °-0.1482 Å °
Refinement TLS groupSelection details: { A|* }

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