8SLO

Plasmodium falciparum M1 aminopeptidase bound to selective inhibitor MIPS2673

8SLO の概要

• エントリーDOI: 10.2210/pdb8slo/pdb
• 分子名称: M1 family aminopeptidase, ZINC ION, 2-hydroxy-N-[(1R)-2-(hydroxyamino)-2-oxo-1-(3',4',5'-trifluoro[1,1'-biphenyl]-4-yl)ethyl]-2-methylpropanamide, ... (6 entities in total)
• 機能のキーワード: plasmodium falciparum, malaria, metallo-exopeptidase, m1 aminopeptidase, aminopeptidase, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Plasmodium falciparum (malaria parasite P. falciparum)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 127849.26

構造登録者

McGowan, S.M.,Drinkwater, N. (登録日: 2023-04-24, 公開日: 2024-04-03, 最終更新日: 2024-07-24)

主引用文献

Giannangelo, C.,Challis, M.P.,Siddiqui, G.,Edgar, R.,Malcolm, T.R.,Webb, C.T.,Drinkwater, N.,Vinh, N.,Macraild, C.,Counihan, N.,Duffy, S.,Wittlin, S.,Devine, S.M.,Avery, V.M.,De Koning-Ward, T.,Scammells, P.,McGowan, S.,Creek, D.J.
Chemoproteomics validates selective targeting of Plasmodium M1 alanyl aminopeptidase as an antimalarial strategy.
Elife, 13:-, 2024

PubMed Abstract: New antimalarial drug candidates that act via novel mechanisms are urgently needed to combat malaria drug resistance. Here, we describe the multi-omic chemical validation of M1 alanyl metalloaminopeptidase as an attractive drug target using the selective inhibitor, MIPS2673. MIPS2673 demonstrated potent inhibition of recombinant (A-M1) and (A-M1) M1 metalloaminopeptidases, with selectivity over other and human aminopeptidases, and displayed excellent in vitro antimalarial activity with no significant host cytotoxicity. Orthogonal label-free chemoproteomic methods based on thermal stability and limited proteolysis of whole parasite lysates revealed that MIPS2673 solely targets A-M1 in parasites, with limited proteolysis also enabling estimation of the binding site on A-M1 to within ~5 Å of that determined by X-ray crystallography. Finally, functional investigation by untargeted metabolomics demonstrated that MIPS2673 inhibits the key role of A-M1 in haemoglobin digestion. Combined, our unbiased multi-omic target deconvolution methods confirmed the on-target activity of MIPS2673, and validated selective inhibition of M1 alanyl metalloaminopeptidase as a promising antimalarial strategy.

PubMed: 38976500
DOI: 10.7554/eLife.92990

実験手法

X-RAY DIFFRACTION (1.55 Å)