6lke

in meso full-length rat KMO in complex with an inhibitor identified via DNA-encoded chemical library screening

spinqualitylabelsall models 6lke, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6lke is a 2 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3Å Ligands: CL, EGU, FAD, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function KMO_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] Publication Abstract from PubMed 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 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Monooxygenase 3D structures

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