Mapping structural and dynamic divergence across the MBOAT family

Ansell, T. Bertie; Healy, Megan; Coupland, Claire E.; Sansom, Mark S. P.; Siebold, Christian

doi:10.1016/j.str.2024.03.014

Title: Mapping structural and dynamic divergence across the MBOAT family

Journal Article · 17 April 2024 · Structure

DOI: https://doi.org/10.1016/j.str.2024.03.014 · OSTI ID:2440879

^[1]; Healy, Megan ^[2]; Coupland, Claire E. ^[3]; Sansom, Mark S. P. ^[2]; Siebold, Christian ^[4]

Univ. of Oxford (United Kingdom); SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL); Stanford Univ., CA (United States); SLAC
Univ. of Oxford (United Kingdom)
Wellcome Centre for Human Genetics, Oxford (United Kingdom); Hospital for Sick Children, Toronto (Canada)
Wellcome Centre for Human Genetics, Oxford (United Kingdom)

Membrane-bound O-acyltransferases (MBOATs) are membrane-embedded enzymes that catalyze acyl chain transfer to a diverse group of substrates, including lipids, small molecules, and proteins. MBOATs share a conserved structural core, despite wide-ranging functional specificity across both prokaryotes and eukaryotes. The structural basis of catalytic specificity, regulation and interactions with the surrounding environment remain uncertain. Here, we combine comparative molecular dynamics (MD) simulations with bioinformatics to assess molecular and interactional divergence across the family. In simulations, MBOATs differentially distort the bilayer depending on their substrate type. Additionally, we identify lipid binding sites surrounding reactant gates in the surrounding membrane. Complementary bioinformatic analyses reveal a conserved role for re-entrant loop-2 in MBOAT fold stabilization and a key hydrogen bond bridging DGAT1 dimerization. Finally, we predict differences in MBOAT solvation and water gating properties. These data are pertinent to the design of MBOAT-specific inhibitors that encompass dynamic information within cellular mimetic environments.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 2440879

Journal Information:: Structure, Journal Name: Structure Journal Issue: 7 Vol. 32; ISSN 0969-2126

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
MBOAT
bilayer
catalysis
enzyme
lipids
membrane protein
molecular dynamics
simulation

Title: Mapping structural and dynamic divergence across the MBOAT family

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