8CRL
Crystal structure of LplA1 in complex with the inhibitor C3 (Listeria monocytogenes)
Summary for 8CRL
| Entry DOI | 10.2210/pdb8crl/pdb |
| Related | 8CRI 8CRJ |
| Descriptor | lipoate--protein ligase, ~{N}-[3-[2-(6-aminopurin-9-yl)ethanoylamino]propyl]-5-[(3~{R})-1,2-dithiolan-3-yl]pentanamide, CALCIUM ION, ... (6 entities in total) |
| Functional Keywords | lipoate, salvage, anti-infectives, drug development, inhibitor, ligase |
| Biological source | Listeria monocytogenes |
| Total number of polymer chains | 2 |
| Total formula weight | 77464.68 |
| Authors | Dienemann, J.-N.,Chen, S.-Y.,Hitzenberger, M.,Sievert, M.L.,Hacker, S.M.,Prigge, S.T.,Zacharias, M.,Groll, M.,Sieber, S.A. (deposition date: 2023-03-08, release date: 2023-06-07, Last modification date: 2023-09-20) |
| Primary citation | Dienemann, J.N.,Chen, S.Y.,Hitzenberger, M.,Sievert, M.L.,Hacker, S.M.,Prigge, S.T.,Zacharias, M.,Groll, M.,Sieber, S.A. A Chemical Proteomic Strategy Reveals Inhibitors of Lipoate Salvage in Bacteria and Parasites. Angew.Chem.Int.Ed.Engl., 62:e202304533-e202304533, 2023 Cited by PubMed Abstract: The development of novel anti-infectives requires unprecedented strategies targeting pathways which are solely present in pathogens but absent in humans. Following this principle, we developed inhibitors of lipoic acid (LA) salvage, a crucial pathway for the survival of LA auxotrophic bacteria and parasites but non-essential in human cells. An LA-based probe was selectively transferred onto substrate proteins via lipoate protein ligase (LPL) in intact cells, and their binding sites were determined by mass spectrometry. Probe labeling served as a proxy of LPL activity, enabling in situ screenings for cell-permeable LPL inhibitors. Profiling a focused compound library revealed two substrate analogs (LAMe and C3) as inhibitors, which were further validated by binding studies and co-crystallography. Importantly, LAMe exhibited low toxicity in human cells and achieved killing of Plasmodium falciparum in erythrocytes with an EC value of 15 μM, making it the most effective LPL inhibitor reported to date. PubMed: 37249408DOI: 10.1002/anie.202304533 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.6 Å) |
Structure validation
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