6lkd
From Proteopedia
in meso full-length rat KMO in complex with a pyrazoyl benzoic acid inhibitor
Structural highlights
FunctionKMO_RAT Catalyzes the hydroxylation of L-kynurenine (L-Kyn) to form 3-hydroxy-L-kynurenine (L-3OHKyn). Required for synthesis of quinolinic acid, a neurotoxic NMDA receptor antagonist and potential endogenous inhibitor of NMDA receptor signaling in axonal targeting, synaptogenesis and apoptosis during brain development. Quinolinic acid may also affect NMDA receptor signaling in pancreatic beta cells, osteoblasts, myocardial cells, and the gastrointestinal tract.[HAMAP-Rule:MF_03018][1] [2] Publication Abstract from PubMedThe 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 A 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. Full-length in meso structure and mechanism of rat kynurenine 3-monooxygenase inhibition.,Mimasu S, Yamagishi H, Kubo S, Kiyohara M, Matsuda T, Yahata T, Thomson HA, Hupp CD, Liu J, Okuda T, Kakefuda K Commun Biol. 2021 Feb 4;4(1):159. doi: 10.1038/s42003-021-01666-5. PMID:33542467[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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