7OPN

Human Aldehyde Oxidase SNP R1231H in complex with Raloxifene

7OPN の概要

• エントリーDOI: 10.2210/pdb7opn/pdb
• 関連するPDBエントリー: 7ORC
• 分子名称: Aldehyde oxidase, DIMETHYL SULFOXIDE, FE2/S2 (INORGANIC) CLUSTER, ... (11 entities in total)
• 機能のキーワード: human aldehyde oxidase, single nucleotide polymorphism, complex, inhibitor, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 302261.18

構造登録者

Mota, C.,Coelho, C.,Santos Silva, T.,Romao, M.J. (登録日: 2021-06-01, 公開日: 2021-09-01, 最終更新日: 2024-01-31)

主引用文献

Mota, C.,Diniz, A.,Coelho, C.,Santos-Silva, T.,Esmaeeli, M.,Leimkuhler, S.,Cabrita, E.J.,Marcelo, F.,Romao, M.J.
Interrogating the Inhibition Mechanisms of Human Aldehyde Oxidase by X-ray Crystallography and NMR Spectroscopy: The Raloxifene Case.
J.Med.Chem., 64:13025-13037, 2021

PubMed Abstract: Human aldehyde oxidase (hAOX1) is mainly present in the liver and has an emerging role in drug metabolism, since it accepts a wide range of molecules as substrates and inhibitors. Herein, we employed an integrative approach by combining NMR, X-ray crystallography, and enzyme inhibition kinetics to understand the inhibition modes of three hAOX1 inhibitors-thioridazine, benzamidine, and raloxifene. These integrative data indicate that thioridazine is a noncompetitive inhibitor, while benzamidine presents a mixed type of inhibition. Additionally, we describe the first crystal structure of hAOX1 in complex with raloxifene. Raloxifene binds tightly at the entrance of the substrate tunnel, stabilizing the flexible entrance gates and elucidating an unusual substrate-dependent mechanism of inhibition with potential impact on drug-drug interactions. This study can be considered as a proof-of-concept for an efficient experimental screening of prospective substrates and inhibitors of hAOX1 relevant in drug discovery.

PubMed: 34415167
DOI: 10.1021/acs.jmedchem.1c01125

実験手法

X-RAY DIFFRACTION (2.6 Å)