Dataset Information

Inhibition of falcilysin from Plasmodium falciparum by interference with its closed-to-open dynamic transition.

ABSTRACT: In the absence of an efficacious vaccine, chemotherapy remains crucial to prevent and treat malaria. Given its key role in haemoglobin degradation, falcilysin constitutes an attractive target. Here, we reveal the mechanism of enzymatic inhibition of falcilysin by MK-4815, an investigational new drug with potent antimalarial activity. Using X-ray crystallography, we determine two binary complexes of falcilysin in a closed state, bound with peptide substrates from the haemoglobin α and β chains respectively. An antiparallel β-sheet is formed between the substrate and enzyme, accounting for sequence-independent recognition at positions P2 and P1. In contrast, numerous contacts favor tyrosine and phenylalanine at the P1' position of the substrate. Cryo-EM studies reveal a majority of unbound falcilysin molecules adopting an open conformation. Addition of MK-4815 shifts about two-thirds of falcilysin molecules to a closed state. These structures give atomic level pictures of the proteolytic cycle, in which falcilysin interconverts between a closed state conducive to proteolysis, and an open conformation amenable to substrate diffusion and products release. MK-4815 and quinolines bind to an allosteric pocket next to a hinge region of falcilysin and hinders this dynamic transition. These data should inform the design of potent inhibitors of falcilysin to combat malaria.

SUBMITTER: Lin J

PROVIDER: S-EPMC11365994 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Publications

Inhibition of falcilysin from Plasmodium falciparum by interference with its closed-to-open dynamic transition.

Lin Jianqing J Yan Xinfu X Chung Zara Z Liew Chong Wai CW El Sahili Abbas A Pechnikova Evgeniya V EV Preiser Peter R PR Bozdech Zbynek Z Gao Yong-Gui YG Lescar Julien J

Communications biology 20240831 1

In the absence of an efficacious vaccine, chemotherapy remains crucial to prevent and treat malaria. Given its key role in haemoglobin degradation, falcilysin constitutes an attractive target. Here, we reveal the mechanism of enzymatic inhibition of falcilysin by MK-4815, an investigational new drug with potent antimalarial activity. Using X-ray crystallography, we determine two binary complexes of falcilysin in a closed state, bound with peptide substrates from the haemoglobin α and β chains re ...[more]

PMID: 39217277

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Project description:Introduction: Previous studies have shown significant conditional differences between eyes open, fixated at an image (EO) and eyes closed (EC) in the acquired resting-state functional magnetic resonance imaging (rs-fMRI) data. Aim: We recently showed significant functional network connectivity (FNC) differences between EO and EC across a variety of networks. In this study, we aim at further evaluating differences in dynamic FNC (dFNC) between EO and EC. Materials and Methods: Rs-fMRI were collected from adolescents aged 9-15 years old during both EO and EC conditions, and dFNC was calculated by using the independent component analysis framework. Results: We found that out of five states (clusters), state 1 was observed to be more dominant in the EO condition, whereas state 2 was observed to be more dominant in the EC condition. States 1 and 2 showed significant differences in the mean dwell time based on false discovery rate, and states 1, 2, 3, and 4 differed in the frequency of occurrences. These results are consistent with our previous study of static connectivity in suggesting that EO and EC differences not only are relatively strong but also importantly reveal that these differences vary over time, especially in one particularly transient connectivity pattern. Conclusion: Our results manifest as changes in the proportion of time spent in unique functional connectivity patterns, and they show unique transient functional connectivity patterns in a subset of identified states. Overall, our findings indicate that both static and dynamic rs-fMRI connectivity patterns are strongly impacted by basic conditional differences such as EO and EC. Impact statement Our findings not only suggest that eyes open, fixated at an image (EO) and eyes closed (EC) condition-related resting state functional magnetic resonance imaging differences are relatively strong, but they also reveal an important attribute of these conditions that these differences vary over time, especially in one particularly transient connectivity pattern. Our results manifest as changes in the proportion of time spent in unique functional connectivity patterns, and they show unique transient functional connectivity patterns in a subset of identified states. We believe there is benefit in having the EO/EC as a contrast of interest in future studies, if time allows.

Dataset Information

Inhibition of falcilysin from Plasmodium falciparum by interference with its closed-to-open dynamic transition.

Publications

Inhibition of falcilysin from Plasmodium falciparum by interference with its closed-to-open dynamic transition.

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