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Discovery of Nonretinoid Inhibitors of CRBP1: Structural and Dynamic Insights for Ligand-Binding Mechanisms.

Discovery of Nonretinoid Inhibitors of CRBP1: Structural and Dynamic Insights for Ligand-Binding Mechanisms.

Authors :
Plau J
Morgan CE
Fedorov Y
Banerjee S
Adams DJ
Blaner WS
Yu EW
Golczak M
Source :
ACS chemical biology [ACS Chem Biol] 2023 Oct 20; Vol. 18 (10), pp. 2309-2323. Date of Electronic Publication: 2023 Sep 15.
Publication Year :
2023

Abstract

The dysregulation of retinoid metabolism has been linked to prevalent ocular diseases including age-related macular degeneration and Stargardt disease. Modulating retinoid metabolism through pharmacological approaches holds promise for the treatment of these eye diseases. Cellular retinol-binding protein 1 (CRBP1) is the primary transporter of all- trans -retinol (atROL) in the eye, and its inhibition has recently been shown to protect mouse retinas from light-induced retinal damage. In this report, we employed high-throughput screening to identify new chemical scaffolds for competitive, nonretinoid inhibitors of CRBP1. To understand the mechanisms of interaction between CRBP1 and these inhibitors, we solved high-resolution X-ray crystal structures of the protein in complex with six selected compounds. By combining protein crystallography with hydrogen/deuterium exchange mass spectrometry, we quantified the conformational changes in CRBP1 caused by different inhibitors and correlated their magnitude with apparent binding affinities. Furthermore, using molecular dynamic simulations, we provided evidence for the functional significance of the "closed" conformation of CRBP1 in retaining ligands within the binding pocket. Collectively, our study outlines the molecular foundations for understanding the mechanism of high-affinity interactions between small molecules and CRBPs, offering a framework for the rational design of improved inhibitors for this class of lipid-binding proteins.

Details

Language :
English
ISSN :
1554-8937
Volume :
18
Issue :
10
Database :
MEDLINE
Journal :
ACS chemical biology
Publication Type :
Academic Journal
Accession number :
37713257
Full Text :
https://doi.org/10.1021/acschembio.3c00402