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- PDB-9bhi: Crystal structure of the MerTK kinase domain with SA4488 -

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Basic information

Entry
Database: PDB / ID: 9bhi
TitleCrystal structure of the MerTK kinase domain with SA4488
ComponentsMer tyrosine kinase domain
KeywordsTRANSFERASE / Receptor Tyrosine Kinase / ATP competitive 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 / cell surface receptor protein tyrosine kinase signaling pathway / Cell surface interactions at the vascular wall / establishment of localization in cell / 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 / transmembrane-ephrin receptor activity / GPI-linked 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 migration / nervous system development / cell-cell signaling / retina development in camera-type eye / 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. / Tyrosine-protein kinase, active site / Immunoglobulin subtype / Immunoglobulin / 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
: / Tyrosine-protein kinase Mer
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.07 Å
AuthorsJakob, C.G. / Qui, W. / Jain, R.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of A-910, a Highly Potent and Orally Bioavailable Dual MerTK/Axl-Selective Tyrosine Kinase Inhibitor.
Authors: Yu, Y. / Jang, M. / Miyashiro, J. / Clark, R.F. / Zhu, G.D. / Gong, J. / Dai, Y. / Frey, R.R. / Penning, T.D. / Kim, H. / Lee, H.K. / Kim, J.K. / Ryu, K.M. / Park, S.J. / Yoon, T. / Li, T. / ...Authors: Yu, Y. / Jang, M. / Miyashiro, J. / Clark, R.F. / Zhu, G.D. / Gong, J. / Dai, Y. / Frey, R.R. / Penning, T.D. / Kim, H. / Lee, H.K. / Kim, J.K. / Ryu, K.M. / Park, S.J. / Yoon, T. / Li, T. / Kurnick, M.D. / Kapecki, N.J. / Li, L. / Gorman, J.V. / Montgomery, D.A. / Manaves, V. / Bromberg, K.D. / Doktor, S.Z. / Thakur, A. / Wang, J. / Smith, H.A. / Buchanan, F.G. / Ferguson, D.C. / Torrent, M. / Jakob, C.G. / Qiu, W. / Upadhyay, A.K. / Martin, R.L. / Lai, A. / Michaelides, M.R.
History
DepositionApr 20, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 9, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2024Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Mer tyrosine kinase domain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,1144
Polymers37,4071
Non-polymers7073
Water3,585199
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)79.555, 79.555, 135.422
Angle α, β, γ (deg.)90, 90, 90
Int Tables number96
Space group name H-MP43212

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Components

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


Mass: 37407.020 Da / Num. of mol.: 1 / Fragment: UNP residues 578-872
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MERTK, MER / Cell line (production host): sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q12866, receptor protein-tyrosine kinase
#2: Chemical ChemComp-A1APF / (5P)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-{(1R,2S)-2-[(4'-{2-[4-(2-oxoethyl)piperazin-1-yl]propan-2-yl}[1,1'-biphenyl]-4-yl)methoxy]cyclopentyl}pyridine-3-carboxamide


Mass: 635.798 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C37H45N7O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 199 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.86 Å3/Da / Density % sol: 57.05 %
Crystal growTemperature: 296 K / Method: vapor diffusion / Details: 3.0 M sodium chloride, 0.1 M Bis-Tris, pH 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Mar 8, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.07→68.6 Å / Num. obs: 27321 / % possible obs: 100 % / Redundancy: 6.7 % / Biso Wilson estimate: 42.07 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.096 / Net I/σ(I): 12.9
Reflection shellResolution: 2.07→2.1 Å / Rmerge(I) obs: 1.476 / Num. unique obs: 1544

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
XDSdata reduction
Aimlessdata scaling
PDB_EXTRACT3.27data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.07→68.59 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.939 / SU R Cruickshank DPI: 0.163 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.175 / SU Rfree Blow DPI: 0.148 / SU Rfree Cruickshank DPI: 0.143
RfactorNum. reflection% reflectionSelection details
Rfree0.2303 1368 -RANDOM
Rwork0.21 ---
obs0.2111 27321 100 %-
Displacement parametersBiso mean: 47.66 Å2
Baniso -1Baniso -2Baniso -3
1--4.918 Å20 Å20 Å2
2---4.918 Å20 Å2
3---9.8361 Å2
Refine analyzeLuzzati coordinate error obs: 0.27 Å
Refinement stepCycle: LAST / Resolution: 2.07→68.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2223 0 49 199 2471
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0082322HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.883144HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d811SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes387HARMONIC5
X-RAY DIFFRACTIONt_it2322HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion293SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact2034SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion2.79
X-RAY DIFFRACTIONt_other_torsion17.11
LS refinement shellResolution: 2.07→2.08 Å
RfactorNum. reflection% reflection
Rfree0.313 19 -
Rwork0.2567 --
obs0.2587 547 100 %

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