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TitleStructures revealing mechanisms of resistance and collateral sensitivity of Plasmodium falciparum to proteasome inhibitors.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 8302, Year 2023
Publish dateDec 14, 2023
AuthorsHao-Chi Hsu / Daqiang Li / Wenhu Zhan / Jianxiang Ye / Yi Jing Liu / Annie Leung / Junling Qin / Benigno Crespo / Francisco-Javier Gamo / Hao Zhang / Liwang Cui / Alison Roth / Laura A Kirkman / Huilin Li / Gang Lin /
PubMed AbstractThe proteasome of the malaria parasite Plasmodium falciparum (Pf20S) is an advantageous drug target because its inhibition kills P. falciparum in multiple stages of its life cycle and synergizes with ...The proteasome of the malaria parasite Plasmodium falciparum (Pf20S) is an advantageous drug target because its inhibition kills P. falciparum in multiple stages of its life cycle and synergizes with artemisinins. We recently developed a macrocyclic peptide, TDI-8304, that is highly selective for Pf20S over human proteasomes and is potent in vitro and in vivo against P. falciparum. A mutation in the Pf20S β6 subunit, A117D, confers resistance to TDI-8304, yet enhances both enzyme inhibition and anti-parasite activity of a tripeptide vinyl sulfone β2 inhibitor, WLW-vs. Here we present the high-resolution cryo-EM structures of Pf20S with TDI-8304, of human constitutive proteasome with TDI-8304, and of Pf20Sβ6 with WLW-vs that give insights into the species selectivity of TDI-8304, resistance to it, and the collateral sensitivity associated with resistance, including that TDI-8304 binds β2 and β5 in wild type Pf20S as well as WLW-vs binds β2 and β5 in Pf20Sβ6. We further show that TDI-8304 kills P. falciparum as quickly as chloroquine and artemisinin and is active against P. cynomolgi at the liver stage. This increases interest in using these structures to facilitate the development of Pf20S inhibitors that target multiple proteasome subunits and limit the emergence of resistance.
External linksNat Commun / PubMed:38097652 / PubMed Central
MethodsEM (single particle)
Resolution2.04 - 2.58 Å
Structure data

29764

8g6e

EMDB-29764, PDB-8g6e:
Structure of the Plasmodium falciparum 20S proteasome complexed with inhibitor TDI-8304
Method: EM (single particle) / Resolution: 2.18 Å

29765

8g6f

EMDB-29765, PDB-8g6f:
Structure of the Plasmodium falciparum 20S proteasome beta-6 A117D mutant complexed with inhibitor WLW-vs
Method: EM (single particle) / Resolution: 2.58 Å

42148

8ud9

EMDB-42148, PDB-8ud9:
Structure of human constitutive 20S proteasome complexed with the inhibitor TDI-8304
Method: EM (single particle) / Resolution: 2.04 Å

Chemicals

ChemComp-YRE:
(7S,10S,13S)-N-cyclopentyl-10-[2-(morpholin-4-yl)ethyl]-9,12-dioxo-13-(2-oxopyrrolidin-1-yl)-2-oxa-8,11-diazabicyclo[13.3.1]nonadeca-1(19),15,17-triene-7-carboxamide

ChemComp-HOH:
WATER

ChemComp-7F1:
(2S)-N-[(E,2S)-1-(1H-indol-3-yl)-4-methylsulfonyl-but-3-en-2-yl]-2-[[(2S)-3-(1H-indol-3-yl)-2-(2-morpholin-4-ylethanoylamino)propanoyl]amino]-4-methyl-pentanamide

Source
  • plasmodium falciparum nf54 (eukaryote)
  • plasmodium falciparum dd2 (eukaryote)
  • homo sapiens (human)
KeywordsHYDROLASE/HYDROLASE INHIBITOR / proteasome / inhibitor / 20S / HYDROLASE / HYDROLASE-HYDROLASE INHIBITOR complex / beta-6 A117D / 20S proteasome / human / complex

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