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Ancestral-sequence reconstruction unveils the structural basis of function in mammalian FMOs.

Abstract：

:Flavin-containing monooxygenases (FMOs) are ubiquitous in all domains of life and metabolize a myriad of xenobiotics, including toxins, pesticides and drugs. However, despite their pharmacological importance, structural information remains bereft. To further our understanding behind their biochemistry and diversity, we used ancestral-sequence reconstruction, kinetic and crystallographic techniques to scrutinize three ancient mammalian FMOs: AncFMO2, AncFMO3-6 and AncFMO5. Remarkably, all AncFMOs could be crystallized and were structurally resolved between 2.7- and 3.2-Å resolution. These crystal structures depict the unprecedented topology of mammalian FMOs. Each employs extensive membrane-binding features and intricate substrate-profiling tunnel networks through a conspicuous membrane-adhering insertion. Furthermore, a glutamate-histidine switch is speculated to induce the distinctive Baeyer-Villiger oxidation activity of FMO5. The AncFMOs exhibited catalysis akin to human FMOs and, with sequence identities between 82% and 92%, represent excellent models. Our study demonstrates the power of ancestral-sequence reconstruction as a strategy for the crystallization of proteins.

journal_name

Nat Struct Mol Biol

journal_title

Nature structural & molecular biology

authors

Nicoll CR,Bailleul G,Fiorentini F,Mascotti ML,Fraaije MW,Mattevi A

doi

10.1038/s41594-019-0347-2

subject

Has Abstract

pub_date

2020-01-01 00:00:00

pages

14-24

issue

1

eissn

1545-9993

issn

1545-9985

pii

10.1038/s41594-019-0347-2

journal_volume

27

pub_type

杂志文章

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