5XIL
Crystal Structure of Leishmania major Prolyl-tRNA Synthetase (LmPRS)
Summary for 5XIL
| Entry DOI | 10.2210/pdb5xil/pdb |
| Related | 5XIF 5XIG 5XIH 5XII 5XIJ 5XIK 5XIO 5XIP 5XIR |
| Descriptor | Putative prolyl-tRNA synthetase, ZINC ION, ACETATE ION, ... (5 entities in total) |
| Functional Keywords | protein translation, prs, synthetase, inhibitor, infectious disease, ligase |
| Biological source | Leishmania major |
| Total number of polymer chains | 1 |
| Total formula weight | 58768.96 |
| Authors | Jain, V.,Manickam, Y.,Sharma, A. (deposition date: 2017-04-26, release date: 2018-03-07, Last modification date: 2024-11-13) |
| Primary citation | Jain, V.,Yogavel, M.,Kikuchi, H.,Oshima, Y.,Hariguchi, N.,Matsumoto, M.,Goel, P.,Touquet, B.,Jumani, R.S.,Tacchini-Cottier, F.,Harlos, K.,Huston, C.D.,Hakimi, M.A.,Sharma, A. Targeting Prolyl-tRNA Synthetase to Accelerate Drug Discovery against Malaria, Leishmaniasis, Toxoplasmosis, Cryptosporidiosis, and Coccidiosis Structure, 25:1495-1505.e6, 2017 Cited by PubMed Abstract: Developing anti-parasitic lead compounds that act on key vulnerabilities are necessary for new anti-infectives. Malaria, leishmaniasis, toxoplasmosis, cryptosporidiosis and coccidiosis together kill >500,000 humans annually. Their causative parasites Plasmodium, Leishmania, Toxoplasma, Cryptosporidium and Eimeria display high conservation in many housekeeping genes, suggesting that these parasites can be attacked by targeting invariant essential proteins. Here, we describe selective and potent inhibition of prolyl-tRNA synthetases (PRSs) from the above parasites using a series of quinazolinone-scaffold compounds. Our PRS-drug co-crystal structures reveal remarkable active site plasticity that accommodates diversely substituted compounds, an enzymatic feature that can be leveraged for refining drug-like properties of quinazolinones on a per parasite basis. A compound we termed In-5 exhibited a unique double conformation, enhanced drug-like properties, and cleared malaria in mice. It thus represents a new lead for optimization. Collectively, our data offer insights into the structure-guided optimization of quinazolinone-based compounds for drug development against multiple human eukaryotic pathogens. PubMed: 28867614DOI: 10.1016/j.str.2017.07.015 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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