6Y9D

Crystal structure of the quaternary ammonium Rieske monooxygenase CntA in complex with substrate L-Carnitine

6Y9D の概要

• エントリーDOI: 10.2210/pdb6y9d/pdb
• 関連するPDBエントリー: 6Y8J 6Y8S 6Y9C
• 分子名称: Carnitine monooxygenase oxygenase subunit, FE (III) ION, FE2/S2 (INORGANIC) CLUSTER, ... (7 entities in total)
• 機能のキーワード: apo, rieske, iron-sulphur cluster, oxidoreductase
• 由来する生物種: Acinetobacter baumannii
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 545645.17

構造登録者

Quareshy, M.,Shanmugam, M.,Bugg, T.D.,Cameron, A.,Chen, Y. (登録日: 2020-03-06, 公開日: 2020-11-18, 最終更新日: 2024-01-24)

主引用文献

Quareshy, M.,Shanmugam, M.,Townsend, E.,Jameson, E.,Bugg, T.D.H.,Cameron, A.D.,Chen, Y.
Structural basis of carnitine monooxygenase CntA substrate specificity, inhibition, and intersubunit electron transfer.
J.Biol.Chem., 296:100038-100038, 2020

PubMed Abstract: Microbial metabolism of carnitine to trimethylamine (TMA) in the gut can accelerate atherosclerosis and heart disease, and these TMA-producing enzymes are therefore important drug targets. Here, we report the first structures of the carnitine oxygenase CntA, an enzyme of the Rieske oxygenase family. CntA exists in a head-to-tail α trimeric structure. The two functional domains (the Rieske and the catalytic mononuclear iron domains) are located >40 Å apart in the same monomer but adjacent in two neighboring monomers. Structural determination of CntA and subsequent electron paramagnetic resonance measurements uncover the molecular basis of the so-called bridging glutamate (E205) residue in intersubunit electron transfer. The structures of the substrate-bound CntA help to define the substrate pocket. Importantly, a tyrosine residue (Y203) is essential for ligand recognition through a π-cation interaction with the quaternary ammonium group. This interaction between an aromatic residue and quaternary amine substrates allows us to delineate a subgroup of Rieske oxygenases (group V) from the prototype ring-hydroxylating Rieske oxygenases involved in bioremediation of aromatic pollutants in the environment. Furthermore, we report the discovery of the first known CntA inhibitors and solve the structure of CntA in complex with the inhibitor, demonstrating the pivotal role of Y203 through a π-π stacking interaction with the inhibitor. Our study provides the structural and molecular basis for future discovery of drugs targeting this TMA-producing enzyme in human gut.

PubMed: 33158989
DOI: 10.1074/jbc.RA120.016019

実験手法

X-RAY DIFFRACTION (1.97 Å)