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- PDB-7dxl: Fragment-based Lead Discovery of Indazole-based Compounds as AXL ... -

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Basic information

Entry
Database: PDB / ID: 7dxl
TitleFragment-based Lead Discovery of Indazole-based Compounds as AXL Kinase Inhibitors
ComponentsTyrosine-protein kinase Mer
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / MER I650M kinase domain / AXL kinase inhibitors / Fragment based lead discovery / ONCOPROTEIN / TRANSFERASE / TRANSFERASE-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 / 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 / cell surface receptor protein tyrosine kinase signaling pathway / 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 / 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-E56 / Tyrosine-protein kinase Mer
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.146 Å
AuthorsAnantharajan, J. / Baburajendran, N.
CitationJournal: Bioorg.Med.Chem. / Year: 2021
Title: Fragment-based lead discovery of indazole-based compounds as AXL kinase inhibitors.
Authors: Ng, P.S. / Foo, K. / Sim, S. / Wang, G. / Huang, C. / Tan, L.H. / Poulsen, A. / Liu, B. / Tee, D.H.Y. / Ahmad, N.H.B. / Wang, S. / Ke, Z. / Lee, M.A. / Kwek, Z.P. / Joy, J. / Anantharajan, J. ...Authors: Ng, P.S. / Foo, K. / Sim, S. / Wang, G. / Huang, C. / Tan, L.H. / Poulsen, A. / Liu, B. / Tee, D.H.Y. / Ahmad, N.H.B. / Wang, S. / Ke, Z. / Lee, M.A. / Kwek, Z.P. / Joy, J. / Anantharajan, J. / Baburajendran, N. / Pendharkar, V. / Manoharan, V. / Vuddagiri, S. / Sangthongpitag, K. / Hill, J. / Keller, T.H. / Hung, A.W.
History
DepositionJan 19, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 13, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)68,9054
Polymers68,0972
Non-polymers8082
Water181
1
A: Tyrosine-protein kinase Mer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,4522
Polymers34,0481
Non-polymers4041
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase Mer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,4522
Polymers34,0481
Non-polymers4041
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)68.056, 90.938, 101.997
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 34048.426 Da / Num. of mol.: 2 / Mutation: I650M
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MERTK, MER / Production host: Escherichia coli (E. coli)
References: UniProt: Q12866, receptor protein-tyrosine kinase
#2: Chemical ChemComp-E56 / 3-[4-[6-chloranyl-5-[[(3R)-pyrrolidin-3-yl]amino]-1H-indazol-3-yl]pyrazol-1-yl]benzenecarbonitrile


Mass: 403.868 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H18ClN7 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / 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: 2.32 Å3/Da / Density % sol: 46.92 %
Crystal growTemperature: 286 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 0.2 M calcium chloride, 0.1 M HEPES pH 7.0, 20% w/v Polyethylene glycol 6000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX2 / Wavelength: 0.9537 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Oct 28, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 3.146→48.06 Å / Num. obs: 11484 / % possible obs: 99.7 % / Redundancy: 6.6 % / Biso Wilson estimate: 48.25 Å2 / CC1/2: 0.987 / Rmerge(I) obs: 0.223 / Rpim(I) all: 0.094 / Rrim(I) all: 0.242 / Net I/σ(I): 4.9
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
3.15-3.366.30.6171262020110.9410.2640.6722.198.8
8.9-48.0660.07135115810.9950.0320.0781199.5

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Processing

Software
NameVersionClassification
Aimless0.7.2data scaling
PHENIX1.11.1_2575refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5TD2

5td2


Resolution: 3.146→48.06 Å / SU ML: 0.45 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 34.55
RfactorNum. reflection% reflection
Rfree0.3017 1134 9.96 %
Rwork0.2548 --
obs0.2593 11391 99.22 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 132.56 Å2 / Biso mean: 44.947 Å2 / Biso min: 10.46 Å2
Refinement stepCycle: final / Resolution: 3.146→48.06 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4054 0 58 1 4113
Biso mean--41.69 26.78 -
Num. residues----517
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0024201
X-RAY DIFFRACTIONf_angle_d0.4715692
X-RAY DIFFRACTIONf_chiral_restr0.038644
X-RAY DIFFRACTIONf_plane_restr0.004711
X-RAY DIFFRACTIONf_dihedral_angle_d6.3052507
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
3.146-3.28890.38261340.3271121697
3.2889-3.46220.31541420.2724126799
3.4622-3.67910.31351390.24791253100
3.6791-3.9630.28151410.2541285100
3.963-4.36160.31381410.21861279100
4.3616-4.99220.26661420.22731277100
4.9922-6.28740.31191440.2555131099
6.2874-48.060.28581510.2729137099

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