6LKE

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

6LKE の概要

• エントリーDOI: 10.2210/pdb6lke/pdb
• 分子名称: Kynurenine 3-monooxygenase, FLAVIN-ADENINE DINUCLEOTIDE, SULFATE ION, ... (6 entities in total)
• 機能のキーワード: single-pass transmembrane proteins, kmo, fad, flavoprotein, membrane protein
• 由来する生物種: Rattus norvegicus (Rat)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 115665.27

構造登録者

Mimasu, S.,Yamagishi, H.,Kiyohara, M.,Hupp, D.C.,Liu, J.,Kakefuda, K.,Okuda, T. (登録日: 2019-12-19, 公開日: 2020-12-23, 最終更新日: 2023-11-22)

主引用文献

Mimasu, S.,Yamagishi, H.,Kubo, S.,Kiyohara, M.,Matsuda, T.,Yahata, T.,Thomson, H.A.,Hupp, C.D.,Liu, J.,Okuda, T.,Kakefuda, K.
Full-length in meso structure and mechanism of rat kynurenine 3-monooxygenase inhibition.
Commun Biol, 4:159-159, 2021

PubMed Abstract: 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.

PubMed: 33542467
DOI: 10.1038/s42003-021-01666-5

実験手法

X-RAY DIFFRACTION (3 Å)