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bioRxiv · 10.64898/2026.09.05.749645

Structural insights into MBOAT2 catalysis, product retention, and ligand exchange

Liu, F.·Li, J.·Shin, W.·Coria, J.·Chen, L.
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Abstract

MBOAT2 suppresses ferroptosis independently of GPX4 and FSP1 by transferring monounsaturated acyl chains from acyl-CoA donors to lysophospholipid acceptors, but the structural basis of its catalytic cycle remains unclear. Here, we report the first cryo-EM structures of human MBOAT2, capturing endogenous and substrate-induced ligand-bound states. Unexpectedly, as-purified MBOAT2 contains a co-purified phospholipid-like density consistent with a retained product, together with a second density at a putative acyl-donor entry site. Oleoyl-CoA addition reduces the ordered product-like density and reveals donor density, whereas LPE addition increases local heterogeneity near the archway. The inactive H373A mutant contains endogenous donor- and acceptor-like densities along the two access pathways, consistent with substrate preloading. Together, these structures define the catalytic architecture of MBOAT2, support a product-retained, donor-primed working model, and provide templates for structure-guided ligand discovery.

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Liu, F., Li, J., Shin, W., Coria, J., Chen, L.. 2026-09-08. Structural insights into MBOAT2 catalysis, product retention, and ligand exchange. https://doi.org/10.64898/2026.09.05.749645

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