8DOC

Crystal structure of RPE65 in complex with compound 16e and palmitate

8DOC の概要

• エントリーDOI: 10.2210/pdb8doc/pdb
• 分子名称: Retinoid isomerohydrolase, FE (II) ION, 3-CYCLOHEXYL-1-PROPYLSULFONIC ACID, ... (6 entities in total)
• 機能のキーワード: 7-bladed beta propeller, monotopic membrane protein, non-heme iron enzyme, retinoid isomerase, inhibitor, complex, hydrolase
• 由来する生物種: Bos taurus (cattle)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 61746.03

構造登録者

Bassetto, M.,Kiser, P.D. (登録日: 2022-07-12, 公開日: 2023-05-24, 最終更新日: 2024-11-06)

主引用文献

Bassetto, M.,Zaluski, J.,Li, B.,Zhang, J.,Badiee, M.,Kiser, P.D.,Tochtrop, G.P.
Tuning the Metabolic Stability of Visual Cycle Modulators through Modification of an RPE65 Recognition Motif.
J.Med.Chem., 66:8140-8158, 2023

PubMed Abstract: In the eye, the isomerization of all--retinal to 11--retinal is accomplished by a metabolic pathway termed the visual cycle that is critical for vision. RPE65 is the essential - isomerase of this pathway. Emixustat, a retinoid-mimetic RPE65 inhibitor, was developed as a therapeutic visual cycle modulator and used for the treatment of retinopathies. However, pharmacokinetic liabilities limit its further development including: (1) metabolic deamination of the γ-amino-α-aryl alcohol, which mediates targeted RPE65 inhibition, and (2) unwanted long-lasting RPE65 inhibition. We sought to address these issues by more broadly defining the structure-activity relationships of the RPE65 recognition motif via the synthesis of a family of novel derivatives, which were tested and for RPE65 inhibition. We identified a potent secondary amine derivative with resistance to deamination and preserved RPE65 inhibitory activity. Our data provide insights into activity-preserving modifications of the emixustat molecule that can be employed to tune its pharmacological properties.

PubMed: 37279401
DOI: 10.1021/acs.jmedchem.3c00461

実験手法

X-RAY DIFFRACTION (2.1 Å)