Structural insights into MBOAT2 catalysis, product retention, and ligand exchange
- 1UT Southwestern Medical Center
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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BibTeX
@misc{liu2026structural,
title = {{Structural insights into MBOAT2 catalysis, product retention, and ligand exchange}},
author = {F. Liu and J. Li and W. Shin and J. Coria and L. Chen},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.05.749645},
url = {https://www.biorxiv.org/content/10.64898/2026.09.05.749645v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Structural insights into MBOAT2 catalysis, product retention, and ligand exchange
AU - F. Liu
AU - J. Li
AU - W. Shin
AU - J. Coria
AU - L. Chen
PY - 2026
DA - 2026/09/05
PB - bioRxiv
DO - 10.64898/2026.09.05.749645
UR - https://www.biorxiv.org/content/10.64898/2026.09.05.749645v1
AB - 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.
ER -