7Q52
Crystal structure of S/T protein kinase PknG from Mycobacterium tuberculosis in complex with inhibitor L2W
This is a non-PDB format compatible entry.
Summary for 7Q52
| Entry DOI | 10.2210/pdb7q52/pdb |
| Descriptor | Serine/threonine-protein kinase PknG, FE (III) ION, 2-azanyl-3-(4-fluorophenyl)carbonyl-indolizine-1-carboxamide, ... (5 entities in total) |
| Functional Keywords | tuberculosis, inhibitor, l2w, transferase |
| Biological source | Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) |
| Total number of polymer chains | 1 |
| Total formula weight | 36734.39 |
| Authors | Defelipe, L.A.,Burastero, O.,Bento, I.,Garcia-Alai, M.M. (deposition date: 2021-11-02, release date: 2022-06-22, Last modification date: 2024-01-31) |
| Primary citation | Burastero, O.,Defelipe, L.A.,Gola, G.,Tateosian, N.L.,Lopez, E.D.,Martinena, C.B.,Arcon, J.P.,Traian, M.D.,Wetzler, D.E.,Bento, I.,Barril, X.,Ramirez, J.,Marti, M.A.,Garcia-Alai, M.M.,Turjanski, A.G. Cosolvent Sites-Based Discovery of Mycobacterium Tuberculosis Protein Kinase G Inhibitors. J.Med.Chem., 65:9691-9705, 2022 Cited by PubMed Abstract: Computer-aided drug discovery methods play a major role in the development of therapeutically important small molecules, but their performance needs to be improved. Molecular dynamics simulations in mixed solvents are useful in understanding protein-ligand recognition and improving molecular docking predictions. In this work, we used ethanol as a cosolvent to find relevant interactions for ligands toward protein kinase G, an essential protein of (). We validated the hot spots by screening a database of fragment-like compounds and another one of known kinase inhibitors. Next, we performed a pharmacophore-guided docking simulation and found three low micromolar inhibitors, including one with a novel chemical scaffold that we expanded to four derivative compounds. Binding affinities were characterized by intrinsic fluorescence quenching assays, isothermal titration calorimetry, and the analysis of melting curves. The predicted binding mode was confirmed by X-ray crystallography. Finally, the compounds significantly inhibited the viability of in infected THP-1 macrophages. PubMed: 35737472DOI: 10.1021/acs.jmedchem.1c02012 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.35 Å) |
Structure validation
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