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- PDB-9bhk: MerTK in complex with small molecule inhibitor 6-{1-[6-(3-hydroxy... -

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Basic information

Entry
Database: PDB / ID: 9bhk
TitleMerTK in complex with small molecule inhibitor 6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide
ComponentsTyrosine-protein kinase Mer
KeywordsTRANSFERASE/INHIBITOR / Transferase kinase ATP competitive inhibitor / 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 / transmembrane receptor protein tyrosine kinase activity ...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 / transmembrane receptor protein tyrosine kinase activity / substrate adhesion-dependent cell spreading / positive regulation of phagocytosis / cell surface receptor protein tyrosine kinase signaling pathway / Cell surface interactions at the vascular wall / establishment of localization in cell / receptor protein-tyrosine kinase / platelet activation / cell migration / nervous system development / cell-cell signaling / retina development in camera-type eye / spermatogenesis / cell surface receptor signaling pathway / protein phosphorylation / receptor complex / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / 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
: / Tyrosine-protein kinase Mer
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.106 Å
AuthorsJakob, C.G. / Gurbani, D. / Qiu, W.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of Potent Azetidine-Benzoxazole MerTK Inhibitors with In Vivo Target Engagement.
Authors: Frey, R.R. / Jana, N. / Gorman, J.V. / Wang, J. / Smith, H.A. / Bromberg, K.D. / Thakur, A. / Doktor, S.Z. / Indulkar, A.S. / Jakob, C.G. / Upadhyay, A.K. / Qiu, W. / Manaves, V. / Gambino ...Authors: Frey, R.R. / Jana, N. / Gorman, J.V. / Wang, J. / Smith, H.A. / Bromberg, K.D. / Thakur, A. / Doktor, S.Z. / Indulkar, A.S. / Jakob, C.G. / Upadhyay, A.K. / Qiu, W. / Manaves, V. / Gambino Jr., F. / Valentino, S.A. / Montgomery, D. / Zhou, Y. / Li, T. / Buchanan, F.G. / Ferguson, D.C. / Kurnick, M.D. / Kapecki, N. / Lai, A. / Michaelides, M.R. / Penning, T.D.
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: Tyrosine-protein kinase Mer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)38,0416
Polymers37,4071
Non-polymers6345
Water3,063170
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)80.385, 80.385, 135.383
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212

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Components

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


Mass: 37407.020 Da / Num. of mol.: 1 / Fragment: tyrosine kinase domain (UNP residues 578-872)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MERTK, MER / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q12866, receptor protein-tyrosine kinase
#2: Chemical ChemComp-A1APH / 6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide


Mass: 492.530 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H28N8O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-CL / CHLORIDE ION


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


Mass: 18.015 Da / Num. of mol.: 170 / 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: 2.92 Å3/Da / Density % sol: 57.92 %
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 6, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.653→68.713 Å / Num. obs: 37375 / % possible obs: 97.3 % / Redundancy: 12.8 % / Biso Wilson estimate: 50.96 Å2 / Rmerge(I) obs: 0.111 / Rsym value: 0.111 / Net I/σ(I): 10.6
Reflection shellResolution: 1.653→1.821 Å / Redundancy: 13 % / Rmerge(I) obs: 1.677 / Mean I/σ(I) obs: 1.7 / Num. unique obs: 482 / Rsym value: 1.677 / % possible all: 98.24

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Processing

Software
NameVersionClassification
HKL-2000data reduction
SCALEPACKdata scaling
BUSTER2.11.8 (16-JUL-2021)refinement
PDB_EXTRACT3.27data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.106→24.64 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.945 / SU R Cruickshank DPI: 0.171 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.182 / SU Rfree Blow DPI: 0.154 / SU Rfree Cruickshank DPI: 0.149
RfactorNum. reflection% reflectionSelection details
Rfree0.2292 1294 5.04 %RANDOM
Rwork0.2067 ---
obs0.2079 25666 97.2 %-
Displacement parametersBiso max: 102.87 Å2 / Biso mean: 53.45 Å2 / Biso min: 28.83 Å2
Baniso -1Baniso -2Baniso -3
1--5.4429 Å20 Å20 Å2
2---5.4429 Å20 Å2
3---10.8857 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: final / Resolution: 2.106→24.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2204 0 40 170 2414
Biso mean--46.85 54.92 -
Num. residues----277
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d816SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes405HARMONIC5
X-RAY DIFFRACTIONt_it2308HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion292SEMIHARMONIC5
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_contact2023SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2308HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg3127HARMONIC20.88
X-RAY DIFFRACTIONt_omega_torsion2.88
X-RAY DIFFRACTIONt_other_torsion17.21
LS refinement shellResolution: 2.11→2.12 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.3215 32 6.23 %
Rwork0.281 482 -
all0.2831 514 -
obs--98.24 %

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