6M0T
Crystal Structure of Lysyl-tRNA Synthetase from Plasmodium falciparum complexed with L-lysine and Cladosporin derivative (CL-2)
Summary for 6M0T
| Entry DOI | 10.2210/pdb6m0t/pdb |
| Related | 4PG3 |
| Descriptor | Lysine--tRNA ligase, LYSINE, (3R)-3-[(R)-[(2R,6S)-6-methyloxan-2-yl]-oxidanyl-methyl]-6,8-bis(oxidanyl)-3,4-dihydroisochromen-1-one, ... (4 entities in total) |
| Functional Keywords | cladosporin analog, stereochemistry, ligase-ligase inhibitor complex, ligase/ligase inhibitor |
| Biological source | Plasmodium falciparum 3D7 |
| Total number of polymer chains | 4 |
| Total formula weight | 236649.82 |
| Authors | Babbar, P.,Sharma, A.,Manickam, Y. (deposition date: 2020-02-22, release date: 2021-04-21, Last modification date: 2024-10-23) |
| Primary citation | Babbar, P.,Das, P.,Manickam, Y.,Mankad, Y.,Yadav, S.,Parvez, S.,Sharma, A.,Reddy, D.S. Design, Synthesis, and Structural Analysis of Cladosporin-Based Inhibitors of Malaria Parasites. Acs Infect Dis., 7:1777-1794, 2021 Cited by PubMed Abstract: Here we have described a systematic structure activity relationship (SAR) of a set of compounds inspired from cladosporin, a tool compound that targets parasite () lysyl tRNA synthetase (KRS). Four sets of analogues, synthesized based on point changes in the chemical scaffold of cladosporin and other logical modifications and hybridizations, were assessed using high throughput enzymatic and parasitic assays along with pharmacokinetics. Co-crystallization of the most potent compound in our series () with KRS revealed its structural basis of enzymatic binding and potency. Further, we report that has performed better than cladosporin in terms of metabolic stability. It thus represents a new lead for further optimization toward the development of antimalarial drugs. Collectively, along with a lead compound, the series offers insights on how even the slightest chemical modification might play an important role in enhancing or decreasing the potency of a chemical scaffold. PubMed: 33843204DOI: 10.1021/acsinfecdis.1c00092 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.68 Å) |
Structure validation
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