Structure-Based Identification of Inhibitors for the SLC13 Family of Na(+)/Dicarboxylate Cotransporters

Author(s)
Claire Colas, Ana M Pajor, Avner Schlessinger
Abstract

In mammals, citric acid cycle intermediates play a key role in regulating various metabolic processes, such as fatty acid synthesis and glycolysis. Members of the sodium-dependent SLC13 transporter family mediate the transport of di- and tricarboxylates into cells. SLC13 family members have been implicated in lifespan extension and resistance to high-fat diets; thus, they are emerging drug targets for aging and metabolic disorders. We previously characterized key structural determinants of substrate and cation binding for the human NaDC3/SLC13A3 transporter using a homology model. Here, we combine computational modeling and virtual screening with functional and biochemical testing, to identify nine previously unknown inhibitors for multiple members of the SLC13 family from human and mouse. Our results reveal previously unknown substrate selectivity determinants for the SLC13 family, including key residues that mediate ligand binding and transport, as well as promiscuous and specific SLC13 small molecule ligands. The newly discovered ligands can serve as chemical tools for further characterization of the SLC13 family or as lead molecules for the future development of potent inhibitors for the treatment of metabolic diseases and aging. Our results improve our understanding of the structural components that are important for substrate specificity in this physiologically important family as well as in other structurally related transport systems.

Organisation(s)
External organisation(s)
Icahn School of Medicine at Mount Sinai, New York, University of California, San Diego
Journal
Biochemistry
Volume
54
Pages
4900-4908
No. of pages
9
ISSN
0006-2960
DOI
https://doi.org/10.1021/acs.biochem.5b00388
Publication date
08-2015
Peer reviewed
Yes
Austrian Fields of Science 2012
301305 Medical chemistry
Keywords
ASJC Scopus subject areas
Biochemistry
Sustainable Development Goals
SDG 3 - Good Health and Well-being
Portal url
https://ucris.univie.ac.at/portal/en/publications/structurebased-identification-of-inhibitors-for-the-slc13-family-of-nadicarboxylate-cotransporters(09992dd2-c86c-4933-8380-a71e5c078937).html