6YI7
Structure of cathepsin B1 from Schistosoma mansoni (SmCB1) in complex with an azanitrile inhibitor
Summary for 6YI7
| Entry DOI | 10.2210/pdb6yi7/pdb |
| Related | 3QSD 3S3Q 3S3R 4I04 4I05 4I07 5OGQ 5OGR |
| Descriptor | Cathepsin B-like peptidase (C01 family), ACETATE ION, 1-[(2~{S})-1-[[iminomethyl(methyl)amino]-methyl-amino]-4-methyl-1-oxidanylidene-pentan-2-yl]-3-(phenylmethyl)urea, ... (4 entities in total) |
| Functional Keywords | cysteine protease, parasite, inhibitor, azanitrile, hydrolase |
| Biological source | Schistosoma mansoni |
| Total number of polymer chains | 1 |
| Total formula weight | 28958.77 |
| Authors | Jilkova, A.,Rezacova, P.,Pachl, P.,Fanfrlik, J.,Rubesova, P.,Guetschow, M.,Mares, M. (deposition date: 2020-04-01, release date: 2020-12-16, Last modification date: 2024-11-06) |
| Primary citation | Jilkova, A.,Horn, M.,Fanfrlik, J.,Kuppers, J.,Pachl, P.,Rezacova, P.,Lepsik, M.,Fajtova, P.,Rubesova, P.,Chanova, M.,Caffrey, C.R.,Gutschow, M.,Mares, M. Azanitrile Inhibitors of the SmCB1 Protease Target Are Lethal to Schistosoma mansoni : Structural and Mechanistic Insights into Chemotype Reactivity. Acs Infect Dis., 7:189-201, 2021 Cited by PubMed Abstract: Azapeptide nitriles are postulated to reversibly covalently react with the active-site cysteine residue of cysteine proteases and form isothiosemicarbazide adducts. We investigated the interaction of azadipeptide nitriles with the cathepsin B1 drug target (SmCB1) from , a pathogen that causes the global neglected disease schistosomiasis. Azadipeptide nitriles were superior inhibitors of SmCB1 over their parent carba analogs. We determined the crystal structure of SmCB1 in complex with an azadipeptide nitrile and analyzed the reaction mechanism using quantum chemical calculations. The data demonstrate that azadipeptide nitriles, in contrast to their carba counterparts, undergo a change from - to -configuration upon binding, which gives rise to a highly favorable energy profile of noncovalent and covalent complex formation. Finally, azadipeptide nitriles were considerably more lethal than their carba analogs against the schistosome pathogen in culture, supporting the further development of this chemotype as a treatment for schistosomiasis. PubMed: 33301315DOI: 10.1021/acsinfecdis.0c00644 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.29 Å) |
Structure validation
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