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- PDB-5td2: Structure-based optimization of 1H-imidazole-2-carboxamides as Ax... -

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Basic information

Entry
Database: PDB / ID: 5td2
TitleStructure-based optimization of 1H-imidazole-2-carboxamides as Axl kinase inhibitors utilizing a Mer mutant surrogate
ComponentsTyrosine-protein kinase Mer
KeywordsTransferase/Transferase Inhibitor / kinase / inhibitor / surrogate / oncology / 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 / 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-7AE / Tyrosine-protein kinase Mer
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.68 Å
AuthorsHoffman, I.D. / Lawson, J.D.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2017
Title: Structure-based optimization of 1H-imidazole-2-carboxamides as Axl kinase inhibitors utilizing a Mer mutant surrogate.
Authors: Keung, W. / Boloor, A. / Brown, J. / Kiryanov, A. / Gangloff, A. / Lawson, J.D. / Skene, R. / Hoffman, I. / Atienza, J. / Kahana, J. / De Jong, R. / Farrell, P. / Balakrishna, D. / Halkowycz, P.
History
DepositionSep 16, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 25, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id

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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)66,1593
Polymers65,6402
Non-polymers5191
Water43224
1
A: Tyrosine-protein kinase Mer
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,3392
Polymers32,8201
Non-polymers5191
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein kinase Mer


Theoretical massNumber of molelcules
Total (without water)32,8201
Polymers32,8201
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)51.157, 91.942, 69.655
Angle α, β, γ (deg.)90.000, 99.510, 90.000
Int Tables number4
Space group name H-MP1211
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
12A
22B
13A
23B
14A
24B
15A
25B
16A
26B

NCS domain segments:

Component-ID: _ / Refine code: _

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11LEULEUILEILEAA577 - 5921 - 16
21LEULEUILEILEBB577 - 5921 - 16
12SERSERTHRTHRAA600 - 62024 - 44
22SERSERTHRTHRBB600 - 62024 - 44
13ALAALACYSCYSAA638 - 65662 - 80
23ALAALACYSCYSBB638 - 65662 - 80
14PROPROARGARGAA667 - 68791 - 111
24PROPROARGARGBB667 - 68791 - 111
15HISHISASPASPAA694 - 741118 - 165
25HISHISASPASPBB694 - 741118 - 165
16TYRTYRSERSERAA777 - 860201 - 284
26TYRTYRSERSERBB777 - 860201 - 284

NCS ensembles :
ID
1
2
3
4
5
6

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Components

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


Mass: 32820.141 Da / Num. of mol.: 2 / Fragment: UNP residues 577-861
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MERTK, MER / Plasmid: pSX71 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)
References: UniProt: Q12866, receptor protein-tyrosine kinase
#2: Chemical ChemComp-7AE / N-[2-{4-[(2S)-4-(methylsulfonyl)morpholin-2-yl]-1,3-thiazol-2-yl}-4-(morpholin-4-yl)phenyl]-1H-imidazole-2-carboxamide


Mass: 518.609 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H26N6O5S2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 24 / Source method: isolated from a natural source / Formula: H2O

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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: 2.46 Å3/Da / Density % sol: 50.03 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: 29% PEG 400 0.2M MgCl2 0.1M Tris pH 8.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.9764848 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 20, 2010
RadiationMonochromator: Asymmetric cut single crystal Si(220) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9764848 Å / Relative weight: 1
ReflectionResolution: 2.68→50 Å / Num. obs: 16671 / % possible obs: 92.8 % / Redundancy: 2.9 % / Rmerge(I) obs: 0.103 / Χ2: 1.033 / Net I/av σ(I): 9.305 / Net I/σ(I): 9.5 / Num. measured all: 48133
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsDiffraction-ID% possible all
2.68-2.732.10.439162.4
2.73-2.782.30.484173.9
2.78-2.832.30.481177.5
2.83-2.892.60.421185.1
2.89-2.952.70.386189
2.95-3.022.80.374192.6
3.02-3.092.90.313197.1
3.09-3.1830.284198.4
3.18-3.2730.231199.7
3.27-3.383.10.179199.7
3.38-3.53.10.145199.7
3.5-3.643.10.133199
3.64-3.83.10.124199.3
3.8-43.10.11198.8
4-4.2530.09197.8
4.25-4.5830.078198
4.58-5.0430.078197.9
5.04-5.773.10.077197.5
5.77-7.2730.07197.3
7.27-502.90.058195.3

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
REFMAC5.8.0103refinement
PDB_EXTRACT3.2data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.68→30 Å / Cor.coef. Fo:Fc: 0.907 / Cor.coef. Fo:Fc free: 0.86 / SU B: 19.043 / SU ML: 0.374 / SU R Cruickshank DPI: 13.7934 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 13.793 / ESU R Free: 0.419
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2999 805 4.8 %RANDOM
Rwork0.2481 ---
obs0.2507 15822 92.42 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 160.78 Å2 / Biso mean: 64.709 Å2 / Biso min: 26.76 Å2
Baniso -1Baniso -2Baniso -3
1-7.47 Å20 Å2-2.06 Å2
2---2.68 Å20 Å2
3----3.87 Å2
Refinement stepCycle: final / Resolution: 2.68→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3892 0 35 24 3951
Biso mean--54.72 47.65 -
Num. residues----482
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0194009
X-RAY DIFFRACTIONr_bond_other_d0.0020.023877
X-RAY DIFFRACTIONr_angle_refined_deg1.1741.995410
X-RAY DIFFRACTIONr_angle_other_deg0.97238930
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.65471
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.43723.793174
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.48315738
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.9891525
X-RAY DIFFRACTIONr_chiral_restr0.0630.2610
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.024323
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02870
X-RAY DIFFRACTIONr_mcbond_it4.366.151917
X-RAY DIFFRACTIONr_mcbond_other4.3616.151916
X-RAY DIFFRACTIONr_mcangle_it6.9049.2032377
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A16560.11
12B16560.11
21A19680.09
22B19680.09
31A15320.14
32B15320.14
41A19320.08
42B19320.08
51A50920.07
52B50920.07
61A97200.06
62B97200.06
LS refinement shellResolution: 2.679→2.748 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.342 47 -
Rwork0.342 794 -
all-841 -
obs--63.62 %

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