4K1F
Crystal structure of reduced tryparedoxin peroxidase from leishmania major at 2.34 A resolution
Summary for 4K1F
| Entry DOI | 10.2210/pdb4k1f/pdb |
| Related | 3TUE |
| Descriptor | Tryparedoxin peroxidase, TRIETHYLENE GLYCOL, CHLORIDE ION, ... (6 entities in total) |
| Functional Keywords | thioredoxin fold, peroxidase, oxidoreductase |
| Biological source | Leishmania major |
| Total number of polymer chains | 5 |
| Total formula weight | 111893.94 |
| Authors | Ilari, A.,Fiorillo, A.,Di Chiaro, F. (deposition date: 2013-04-05, release date: 2014-04-09, Last modification date: 2023-11-08) |
| Primary citation | Brindisi, M.,Brogi, S.,Relitti, N.,Vallone, A.,Butini, S.,Gemma, S.,Novellino, E.,Colotti, G.,Angiulli, G.,Di Chiaro, F.,Fiorillo, A.,Ilari, A.,Campiani, G. Structure-based discovery of the first non-covalent inhibitors of Leishmania major tryparedoxin peroxidase by high throughput docking Sci Rep, 5:9705-9705, 2015 Cited by PubMed Abstract: Leishmaniasis is a neglected vector-born disease caused by a protozoan of the genus Leishmania and affecting more than 1.300.000 people worldwide. The couple tryparedoxin/tryparedoxin peroxidase is essential for parasite survival in the host since it neutralizes the hydrogen peroxide produced by macrophages during the infection. Herein we report a study aimed at discovering the first class of compounds able to non-covalently inhibit tryparedoxin peroxidase. We have solved the high-resolution structure of Tryparedoxin peroxidase I from Leishmania major (LmTXNPx) in the reduced state and in fully folded conformation. A first series of compounds able to inhibit LmTXNPx was identified by means of the high throughput docking technique. The inhibitory activity of these compounds was validated by a Horseradish peroxidase-based enzymatic assay and their affinity for LmTXNPx calculated by surface plasmon resonance experiments. On the basis of these results, the analysis of the enzyme-inhibitor docked models allowed us to rationally design and synthesize a series of N,N-disubstituted 3-aminomethyl quinolones. These compounds showed an inhibitory potency against LmTXNPx in the micromolar range. Among them, compound 12 represents the first non-covalent LmTXNPx inhibitor reported to date and could pave the way to the discovery of a new class of drugs against leishmaniasis. PubMed: 25951439DOI: 10.1038/srep09705 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.34 Å) |
Structure validation
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