9Q6F
Structure of Plasmodium falciparum 20S proteasome bound to an asparagine-ethylenediamine based inhibitor TDI6245
This is a non-PDB format compatible entry.
Summary for 9Q6F
| Entry DOI | 10.2210/pdb9q6f/pdb |
| EMDB information | 72277 |
| Descriptor | Proteasome subunit alpha type-6, Proteasome subunit beta, N~4~-tert-butyl-N~2~-(4-methylbenzene-1-sulfonyl)-N~1~-[2-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-L-aspartamide, ... (15 entities in total) |
| Functional Keywords | plasmodium falciparum antimalarial proteasome inhibitors, hydrolase |
| Biological source | Plasmodium falciparum (malaria parasite P. falciparum) More |
| Total number of polymer chains | 28 |
| Total formula weight | 771459.49 |
| Authors | |
| Primary citation | Zhang, H.,Li, D.,Hsu, H.C.,Vishwanatha, A.,Zhan, W.,Yukawa, T.,Visone, J.,Imaeda, T.,Okamoto, R.,Fajtova, P.,Hara, R.,Kawasaki, M.,Sato, K.,Michino, M.,Garg, S.,Kreutzfeld, O.,Tumwebaze, P.K.,Orena, S.,Okitwi, M.,Aso, K.,Cooper, R.A.,Rosenthal, P.J.,Meinke, P.T.,Foley, M.,O'Donoghue, A.J.,Li, H.,Kirkman, L.A.,Lin, G. Structure-Activity Relationship Study of Antimalarial Asparagine-Derived Proteasome Inhibitors. Acs Omega, 11:45549-45559, 2026 Cited by PubMed Abstract: Malaria remains a significant global health threat, affecting millions of lives each year. The causative agents, parasites, are highly resilient and have developed resistance to nearly all existing antimalarial drugs. The 20S proteasome core (20S), a central component of the parasite's proteostasis pathway, has emerged as a promising therapeutic target. Inhibiting 20S effectively suppresses parasite growth at multiple stages of the parasite life cycle, synergizes with artemisinin-based therapies, and shows no cross-resistance with other antimalarial drug classes. Previously, we identified a novel class of proteasome inhibitors with potent activity against 20S, which we subsequently optimized for improved potency and selectivity over human proteasomes. However, these inhibitors exhibited suboptimal pharmacokinetic properties, potentially attributable to a high number of rotatable bonds and hydrogen bond donors. Here, we describe further optimization of this inhibitor class and provide structural insights into 20S-inhibitor interactions. Cryo-EM structural studies reveal a novel binding pose of the inhibitor at the 20S β5 active site, explaining the enhanced activity of an -cap sulfonamide modification compared to an -cap amide. These findings offer insights into the development of next-generation antimalarial 20S-targeting compounds with improved drug-like properties. PubMed: 42569042DOI: 10.1021/acsomega.6c06226 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.86 Å) |
Structure validation
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