Targeting ligand binding sites in Plasmodium falciparum NCR1 enables antimalarial drug discovery
Kohling, A.; Boulet, C.; Al Makhlouf, M.; Khanppnavar, B.; Chen, Y.; Ganga, E.; Kirchmair, J.; Stockner, T.; Brochet, M.; Korkhov, V. M.
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PfNCR1 is a Plasmodium falciparum cholesterol transporter at the plasma membrane- parasitophorous vacuole interface, which has recently emerged as a promising antimalarial target. Despite an immense interest in development of novel antimalarials targeting PfNCR1, the molecular mechanism of PfNCR1 inhibition remains elusive. Here, we report cryo-EM structures of PfNCR1 in its apo state and bound to three inhibitors: MMV009108, MMV019662 and MMV028038. MMV009108 binds to the "neck" site at the ectodomain-membrane domain interface. MMV028038 displaces the sterol at the ectodomain "ecto" site. Remarkably, MMV019662 binds both sites: it associates near the bound sterol molecule at the ecto site and targets the neck site, thereby altering the sterol-sensing domain conformation. Moreover, we identify a novel antimalarial compound, G856-4236, which targets the ecto site exclusively. These four distinct modes of PfNCR1 inhibition advance our understanding of its conformational plasticity and establish a framework for rational drug discovery targeting PfNCR1 and related transporters.
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