8SLO
Plasmodium falciparum M1 aminopeptidase bound to selective inhibitor MIPS2673
Summary for 8SLO
| Entry DOI | 10.2210/pdb8slo/pdb |
| Descriptor | 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) |
| Functional Keywords | plasmodium falciparum, malaria, metallo-exopeptidase, m1 aminopeptidase, aminopeptidase, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Plasmodium falciparum (malaria parasite P. falciparum) |
| Total number of polymer chains | 1 |
| Total formula weight | 127849.26 |
| Authors | McGowan, S.M.,Drinkwater, N. (deposition date: 2023-04-24, release date: 2024-04-03, Last modification date: 2024-07-24) |
| Primary citation | 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 Cited by 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: 38976500DOI: 10.7554/eLife.92990 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.55 Å) |
Structure validation
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