8W2F

Plasmodium falciparum 20S proteasome bound to an inhibitor

This is a non-PDB format compatible entry.

Summary for 8W2F

• Entry DOI: 10.2210/pdb8w2f/pdb
• EMDB information: 43746
• 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, cytosolic protein/inhibitor
• Biological source: Plasmodium falciparum 3D7; More
• Total number of polymer chains: 28
• Total formula weight: 767152.69

Authors

Han, Y.,Deng, X.,Ray, S.,Chen, Z.,Phillips, M. (deposition date: 2024-02-20, release date: 2024-07-31, Last modification date: 2025-05-28)

Primary citation

Lawong, A.,Gahalawat, S.,Ray, S.,Ho, N.,Han, Y.,Ward, K.E.,Deng, X.,Chen, Z.,Kumar, A.,Xing, C.,Hosangadi, V.,Fairhurst, K.J.,Tashiro, K.,Liszczak, G.,Shackleford, D.M.,Katneni, K.,Chen, G.,Saunders, J.,Crighton, E.,Casas, A.,Robinson, J.J.,Imlay, L.S.,Zhang, X.,Lemoff, A.,Zhao, Z.,Angulo-Barturen, I.,Jimenez-Diaz, M.B.,Wittlin, S.,Campbell, S.F.,Fidock, D.A.,Laleu, B.,Charman, S.A.,Ready, J.M.,Phillips, M.A.
Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria.
Cell Chem Biol, 31:1503-, 2024

PubMed Abstract: Malaria remains a global health concern as drug resistance threatens treatment programs. We identified a piperidine carboxamide (SW042) with anti-malarial activity by phenotypic screening. Selection of SW042-resistant Plasmodium falciparum (Pf) parasites revealed point mutations in the Pf_proteasome β5 active-site (Pfβ5). A potent analog (SW584) showed efficacy in a mouse model of human malaria after oral dosing. SW584 had a low propensity to generate resistance (minimum inoculum for resistance [MIR] >10) and was synergistic with dihydroartemisinin. Pf_proteasome purification was facilitated by His-tag introduction onto β7. Inhibition of Pfβ5 correlated with parasite killing, without inhibiting human proteasome isoforms or showing cytotoxicity. The Pf_proteasome_SW584 cryoelectron microscopy (cryo-EM) structure showed that SW584 bound non-covalently distal from the catalytic threonine, in an unexplored pocket at the β5/β6/β3 subunit interface that has species differences between Pf and human proteasomes. Identification of a reversible, species selective, orally active series with low resistance propensity provides a path for drugging this essential target.

PubMed: 39084225
DOI: 10.1016/j.chembiol.2024.07.001

Experimental method

ELECTRON MICROSCOPY (3.1 Å)