In humans, there are over 460 Solute Carrier (SLC) transporters that mediate the import and efflux of solutes, including neurotransmitters, nutrients, and ions. The SLCs are emerging as key therapeutic targets for a variety of diseases and disorders. For example, nutrient SLC transporters play a major role in reprogrammed metabolic networks in cancer, autoimmune disease, and heart ischemia, by supplying cells with nutrients that are used to build biomass or serve as signaling molecules that enhance cell proliferation and differentiation, or regulate cell death. Our broad goal is to describe the substrate and inhibitor specificity determinants in nutrient transporters and develop novel strategies to modulate their functions. We take an integrative approach that includes computational biology and organic chemistry, coupled with biochemical and biophysical approaches, and in vitro models of disease, to characterize the Alanine-Serine-Cysteine Transporter 2 (ASCT2, SLC1A5).
In Aim 1 of this project, we will generate and refine homology models for the human SLC1 family in multiple conformations. We will describe structural features of the models? substrate binding site and recently discovered allosteric site(s), that determine substrate and inhibitor specificity. Key residues will be tested with site-directed mutagenesis and electrophysiological approaches. Finally, we will develop a publicly-accessible database that includes homology models for all modelable human SLC transporters, and maps disease-related mutations onto the models and provides their predicted functional effect.
In Aim 2, we will rationally design small molecule tool compounds that modulate the function of nutrient transporters via distinct mechanisms. This will expand the chemical space of transporter inhibitors and provide a test for the models developed in Aim 1. We will focus on the following approaches: (A) optimizing and characterizing novel conformation-specific inhibitors, such as photoactivatable and fluorescent compounds that interact with the substrate binding site of ASCT2; (B) designing allosteric inhibitors targeting the domain-domain interface in ASCT2, to test the putative elevator mechanism of this transporter; and (C) developing inhibitors with dual specificity for ASCT2 and the L-type Amino Acid Transporter 1 (LAT1, SLC7A5), which we hypothesize to have a pronounced inhibitory effect on cell proliferation due to their cooperativity in reprogrammed metabolic networks. If successful, this project will improve our understanding of structure-function relationships in emerging therapeutic targets. This project will also provide novel chemical probes to further characterize the structure of these proteins and their role in disease, as well as a useful publicly available online resource.
Solute Carrier (SLC) transporters mediate the transport of ions, nutrients, drugs, and toxins, across biological membranes, and play a key role in hyper-proliferative cells, by supporting the increased reliance on glutamine. Our broad goal is to elucidate the mechanisms of transport and chemical modulation of SLC nutrient transporters, by using an integrated experimental and computational approach. This work will allow us to develop computational and chemical tools to study emerging therapeutic targets, characterize structure/function relationships in understudied proteins, and ultimately, provide a unique strategy to deprive nutrients and starve malignant cells, greatly benefitting human health.
|Ung, Peter Man-Un; Rahman, Rayees; Schlessinger, Avner (2018) Redefining the Protein Kinase Conformational Space with Machine Learning. Cell Chem Biol 25:916-924.e2|
|Schlessinger, Avner; Welch, Matthew A; van Vlijmen, Herman et al. (2018) Molecular Modeling of Drug-Transporter Interactions-An International Transporter Consortium Perspective. Clin Pharmacol Ther 104:818-835|
|Sonoshita, Masahiro; Scopton, Alex P; Ung, Peter M U et al. (2018) A whole-animal platform to advance a clinical kinase inhibitor into new disease space. Nat Chem Biol 14:291-298|
|Ilgü, Hüseyin; Jeckelmann, Jean-Marc; Colas, Claire et al. (2018) Effects of Mutations and Ligands on the Thermostability of the l-Arginine/Agmatine Antiporter AdiC and Deduced Insights into Ligand-Binding of Human l-Type Amino Acid Transporters. Int J Mol Sci 19:|
|Colas, Claire; Masuda, Masayuki; Sugio, Kazuaki et al. (2017) Chemical Modulation of the Human Oligopeptide Transporter 1, hPepT1. Mol Pharm 14:4685-4693|
|Singh, Kurnvir; Tanui, Rose; Gameiro, Armanda et al. (2017) Structure activity relationships of benzylproline-derived inhibitors of the glutamine transporter ASCT2. Bioorg Med Chem Lett 27:398-402|
|Colas, Claire; Schlessinger, Avner; Pajor, Ana M (2017) Mapping Functionally Important Residues in the Na+/Dicarboxylate Cotransporter, NaDC1. Biochemistry 56:4432-4441|
|Heimann, Andrea S; Gupta, Achla; Gomes, Ivone et al. (2017) Generation of G protein-coupled receptor antibodies differentially sensitive to conformational states. PLoS One 12:e0187306|
|Colas, Claire; Ung, Peter Man-Un; Schlessinger, Avner (2016) SLC Transporters: Structure, Function, and Drug Discovery. Medchemcomm 7:1069-1081|
|Gundersen, Gregory W; Jagodnik, Kathleen M; Woodland, Holly et al. (2016) GEN3VA: aggregation and analysis of gene expression signatures from related studies. BMC Bioinformatics 17:461|
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