9O3F
Plasmodium falciparum 20S proteasome bound to inhibitor 296
This is a non-PDB format compatible entry.
Summary for 9O3F
| Entry DOI | 10.2210/pdb9o3f/pdb |
| Related | 9O3e |
| EMDB information | 70077 70078 |
| Descriptor | Proteasome endopeptidase complex, Proteasome subunit beta, Proteasome subunit beta type, ... (15 entities in total) |
| Functional Keywords | malaria, plasmodium falciparum, proteasome, drug discovery, cytosolic protein, cytosolic protein-inhibitor complex |
| Biological source | Plasmodium falciparum 3D7 More |
| Total number of polymer chains | 28 |
| Total formula weight | 767332.83 |
| Authors | |
| Primary citation | Gahalawat, S.,Ray, S.,Zhang, X.,Deng, X.,Han, Y.,Chen, Z.,Lawong, A.,Shackleford, D.M.,Katneni, K.,Chen, G.,Li, P.,Ng, A.,Zhong, L.,Hu, M.,McInerney, M.,Wang, W.,Saunders, J.,Collins, D.,Jayaseelan, J.,Noack, C.L.,C Maity, B.,De, N.,Laleu, B.,Campbell, S.F.,Phillips, M.A.,Charman, S.A.,Ready, J.M. Optimization of Species-Selective Reversible Proteasome Inhibitors for the Treatment of Malaria. J.Med.Chem., 2025 Cited by PubMed Abstract: Malaria remains a critical global health challenge, with increasing resistance to frontline therapies necessitating novel drug targets. The proteasome has emerged as a promising target for antimalarial drug discovery. This study describes efforts to optimize a series of species-selective reversible inhibitors targeting the 20S proteasome. Starting from the carboxypiperidine scaffold identified through a high-throughput viability screen, we conducted iterative structure-activity relationship studies, leading to the development of highly potent and selective inhibitors with good oral bioavailability. Lead compounds demonstrated nanomolar potency against blood-stage parasites and selective inhibition of the parasite proteasome over the human counterpart. Cryo-EM structural studies confirmed binding at the β5 subunit, while in vivo pharmacokinetic studies identified promising candidates for further development. These findings support proteasome inhibition as a viable strategy for novel antimalarial drug development. PubMed: 41148577DOI: 10.1021/acs.jmedchem.5c02394 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.28 Å) |
Structure validation
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