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

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 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 9 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 to further characterize the SLC13 family or as lead molecules for 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.

The bacterial dicarboxylate transporter VcINDY uses a two-domain elevator-type mechanism

“…Mammalian homologs of VcINDY are potential drug targets in the treatment of metabolic diseases, age-related diabetes and obesity 16,39 . VcINDY is ~30% identical and shares a number of functional characteristics, such as substrate specificity and coupling ion stoichiometry, with its mammalian homologs, in particular hNaDC3 17 .…”

Mutations in the Na+/Citrate Cotransporter NaCT (SLC13A5) in Pediatric Patients with Epilepsy and Developmental Delay

“…Models were constructed with MODELLER-9v14 (20) using a previously published NaCT-vcINDY alignment and modeling protocol (14,21). In brief, we built 100 models, which were assessed and ranked by the statistical potential Z-DOPE (22).…”

Weighted Gene Correlation Network Analysis (WGCNA) Detected Loss of MAGI2 Promotes Chronic Kidney Disease (CKD) by Podocyte Damage

“…Taking the brown module as an example, which showed functional enrichment in metabolic and oxidation-reduction processes, some hub genes have been also reported to participate in similar processes, e.g. the SLC13 Family (SLC13A3) [28,29], SLC22 Family (SLC22A6) [30] or MSRA that plays a protective role in the progression of UUO-induced kidney fibrosis via suppression of fibrotic responses caused by oxidative stress [31]. Similarly, some hub genes in the yellow module have been identified as pro-inflammatory factors in a variety of human diseases, including CTSS and ITGB2 [32], consistent with the BP term or KEGG pathway enriched in the yellow module.…”