Dataset Information

Molecular basis of inhibition of the amino acid transporter B⁰AT1 (SLC6A19).

ABSTRACT: The epithelial neutral amino acid transporter B⁰AT1 (SLC6A19) is the major transporter for the absorption of neutral amino acids in the intestine and their reabsorption in the kidney. Mouse models have demonstrated that lack of B⁰AT1 can normalize elevated plasma amino acids in rare disorders of amino acid metabolism such as phenylketonuria and urea-cycle disorders, implying a pharmacological approach for their treatment. Here we employ a medicinal chemistry approach to generate B⁰AT1 inhibitors with IC₅₀-values of 31-90 nM. High-resolution cryo-EM structures of B⁰AT1 in the presence of two compounds from this series identified an allosteric binding site in the vestibule of the transporter. Mechanistically, binding of these inhibitors prevents a movement of TM1 and TM6 that is required for the transporter to make a conformational change from an outward open state to the occluded state.

SUBMITTER: Xu J

PROVIDER: S-EPMC11341722 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Molecular basis of inhibition of the amino acid transporter B0AT1 (SLC6A19).

Xu Junyang J Hu Ziwei Z Dai Lu L Yadav Aditya A Jiang Yashan Y Bröer Angelika A Gardiner Michael G MG McLeod Malcolm M Yan Renhong R Bröer Stefan S

Nature communications 20240822 1

The epithelial neutral amino acid transporter B0AT1 (SLC6A19) is the major transporter for the absorption of neutral amino acids in the intestine and their reabsorption in the kidney. Mouse models have demonstrated that lack of B0AT1 can normalize elevated plasma amino acids in rare disorders of amino acid metabolism such as phenylketonuria and urea-cycle disorders, implying a pharmacological approach for their treatment. Here we employ a medicinal chemistry approach to gen ...[more]

PMID: 39174516

Similar Datasets

Project description:B0AT1 (SLC6A19) is a major sodium-coupled neutral amino acid transporter that relies on angiotensin converting enzyme 2 (ACE2) or collectrin for membrane trafficking. Despite its significant role in disorders associated with amino acid metabolism, there is a deficit of comprehensive structure-function understanding of B0AT1 in lipid environment. Herein, we have employed molecular dynamics (MD) simulations to explore the architectural characteristics of B0AT1 in two distinct environments: a simplified POPC bilayer and a complex lipid system replicating the native membrane composition. Notably, our B0AT1 analysis in terms of structural stability and regions of maximum flexibility shows consistency in both the systems with enhanced structural features in the case of complex lipid system. Our findings suggest that diacylglycerol phospholipids significantly alter the pore radius, hydrophobic index, and surface charge distribution of B0AT1, thereby affecting the flexibility of transmembrane helices TM7, TM12, and loop connecting TM7-TM8, crucial for ACE2-B0AT1 interaction. Pro41, Ser190, Arg214, Arg240, Ser413, Pro414, Cys463, and Val582 are among the most prominent lipid binding residues that might influence B0AT1 functionality. We also perceive notable lipid mediated deviation in the degree of tilt and loss of helicity in TM1 and TM6 which might affect the substrate binding sites S1 and S2 in B0AT1. Considerably, destabilization in the structure of B0AT1 in lipid environment was evident upon mutation in TM domain, associated with Hartnup disorder through various structure-based protein stability tools. Our two-tiered approach allowed us to validate the use of POPC as a baseline for initial analyses of SLC transporters. Altogether, our all-atoms MD study provides a platform for future investigations into the structure-function mechanism of B0AT1 in realistic lipid mimetic bilayers and offers a framework for developing new therapeutic agents targeting this transporter.

Dataset Information

Molecular basis of inhibition of the amino acid transporter B⁰AT1 (SLC6A19).

Publications

Molecular basis of inhibition of the amino acid transporter B<sup>0</sup>AT1 (SLC6A19).

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets