Scientific Publication | February 4, 2021

Full-length in meso structure and mechanism of rat kynurenine 3-monooxygenase inhibition

Publication: Nature

The structural mechanisms of single-pass transmembrane enzymes remain elusive. Kynurenine
3-monooxygenase (KMO) is a mitochondrial protein involved in the eukaryotic tryptophan
catabolic pathway and is linked to various diseases. Here, we report the mammalian
full-length structure of KMO in its membrane-embedded form, complexed with compound 3
(identified internally) and compound 4 (identified via DNA-encoded chemical library
screening) at 3.0 Å resolution. Despite predictions suggesting that KMO has two transmembrane
domains, we show that KMO is actually a single-pass transmembrane protein,
with the other transmembrane domain lying laterally along the membrane, where it forms
part of the ligand-binding pocket. Further exploration of compound 3 led to identification of
the brain-penetrant compound, 5. We show that KMO is dimeric, and that mutations at the
dimeric interface abolish its activity. These results will provide insight for the drug discovery
of additional blood-brain-barrier molecules, and help illuminate the complex biology behind
single-pass transmembrane enzymes.

Back to Resources