8ho4
Falcilysin in complex with MMV000848
Structural highlights
FunctionFCLN_PLAF7 In the food vacuole, acts downstream of proteases plasmepsins PMI and PMII and falcipains during the catabolism of host hemoglobin by cleaving peptide fragments of alpha and beta hemoglobin subunits generated by PMI and PMII and falcipains (PubMed:17074076). In the apicoplast, degrades apicoplast transit peptides after their cleavage (PubMed:17074076). Prefers bulky hydrophobic amino acids in the P1' position at both acidic and neutral pH (By similarity). At P2', prefers hydrophobic residues at acidic pH; at neutral pH, these same residues are abundant but prefers Arg (By similarity). At P3', prefers hydrophobic residues, especially Met, at both pH conditions. At P4' and P5', prefers acidic residues at acidic pH, however, at neutral pH, the enzyme is less selective at these positions (By similarity). The optimal site cleavage at acidic pH is YNEHS-|-FFMEE and, at neutral pH, MKRHS-|-FRMRG (By similarity).[UniProtKB:A0A0L7KF24][1] Publication Abstract from PubMedIdentification of new druggable protein targets remains the key challenge in the current antimalarial development efforts. Here we used mass-spectrometry-based cellular thermal shift assay (MS-CETSA) to identify potential targets of several antimalarials and drug candidates. We found that falcilysin (FLN) is a common binding partner for several drug candidates such as MK-4815, MMV000848, and MMV665806 but also interacts with quinoline drugs such as chloroquine and mefloquine. Enzymatic assays showed that these compounds can inhibit FLN proteolytic activity. Their interaction with FLN was explored systematically by isothermal titration calorimetry and X-ray crystallography, revealing a shared hydrophobic pocket in the catalytic chamber of the enzyme. Characterization of transgenic cell lines with lowered FLN expression demonstrated statistically significant increases in susceptibility toward MK-4815, MMV000848, and several quinolines. Importantly, the hydrophobic pocket of FLN appears amenable to inhibition and the structures reported here can guide the development of novel drugs against malaria. Identification of an inhibitory pocket in falcilysin provides a new avenue for malaria drug development.,Wirjanata G, Lin J, Dziekan JM, El Sahili A, Chung Z, Tjia S, Binte Zulkifli NE, Boentoro J, Tham R, Jia LS, Go KD, Yu H, Partridge A, Olsen D, Prabhu N, Sobota RM, Nordlund P, Lescar J, Bozdech Z Cell Chem Biol. 2024 Apr 18;31(4):743-759.e8. doi: , 10.1016/j.chembiol.2024.03.002. Epub 2024 Apr 8. PMID:38593807[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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