The RESOLUTE consortium: unlocking SLC transporters for drug discovery

Superti‐Furga, Giulio; Lackner, Daniel H.; Wiedmer, Tabea; Inglés-Prieto, Álvaro; Barbosa, Bárbara C.M.; Gottardi, Enrico; Goldmann, Ulrich; Gürtl, Bettina; Klavins, Kristaps; Klimek, Christoph; Lindinger, Sabrina; Liñeiro-Retes, Eva; Müller, André C.; Onstein, Svenja; Redinger, Gregor; Reil, Daniela; Sedlyarov, Vitaly; Wolf, Gernot; Crawford, Matthew A.; Everley, Robert A.; Hepworth, David; Liu, Shenping; Noell, Stephen; Piotrowski, Mary; Stanton, Robert V.; Zhang, Hui; Corallino, Salvatore; Faedo, Andrea; Insidioso, Maria; Maresca, Giovanna; Redaelli, Loredana; Sassone, Francesca; Scarabottolo, Lia; Stucchi, Michela; Tarroni, Paola; Tremolada, Sara; Batoulis, Helena; Becker, Andreas; Bender, Eckhard; Chang, Yung-Ning; Ehrmann, Alexander; Müller‐Fahrnow, Anke; Pütter, Vera; Zindel, Diana; Hamilton, Bradford S.; Lenter, Martin; Santacruz, Diana; Viollet, Coralie; Whitehurst, Charles E.; Johnsson, Kai; Leippe, Philipp; Baumgarten, Birgit; Chang, Lena; Ibig, Yvonne; Pfeifer, Martin; Reinhardt, Jürgen; Schönbett, Julian; Selzer, Paul M.; Seuwen, Klaus; Bettembourg, Charles; Biton, Bruno; Czech, J.; Foucauld, Hélène de; Didier, Michel; Licher, Thomas; Mikol, Vincent; Pommereau, Antje; Puech, Frédéric; Yaligara, Veeranagouda; Edwards, A.M.; Bongers, Brandon J.; Heitman, Laura H.; Ijzerman, A. P.; Sijben, Hubert J.; Westen, Gerard J. P. van; Grixti, Justine M.; Kell, Douglas B.; Mughal, Farah; Swainston, Neil; Muelas, Marina Wright; Bohstedt, Tina; Burgess-Brown, N.; Carpenter, Liz; Dürr, Katharina L.; Hansen, Jesper S.; Scacioc, Andreea; Banci, Giulia; Colas, Claire; Digles, Daniela; Ecker, Gerhard; Füzi, Barbara; Gamsjäger, Viktoria; Grandits, Melanie; Martini, Riccardo; Troger, Florentina; Altermatt, Patrick; Doucerain, Cédric; Dürrenberger, Franz; Manolova, Vania; Steck, Anna-Lena; Sundström, Hanna; Wilhelm, Maria; Steppan, Claire M.

doi:10.1038/d41573-020-00056-6

Cited by 78 publications

(63 citation statements)

References 5 publications

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“…For instance, the ReSOLUTE consortium is one of the actions taken to tackle the research on SLCs. This consortium is a public-private partnership created with the goal of improving knowledge of SLC transporters, demonstrating the importance of this field of research (Superti-Furga et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Toward a Systematic Structural and Functional Annotation of Solute Carriers Transporters—Example of the SLC6 and SLC7 Families

Colas

2020

Front. Pharmacol.

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SLC transporters are emerging key drug targets. One important step for drug development is the profound understanding of the structural determinants defining the substrate selectivity of each transporter. Recently, the improvement of computational power and experimental methods such as X-ray and cryo-EM crystallography permitted to conduct structure-based studies on specific transporters having important pharmacological impact. However, a lot remains to be discovered regarding their dynamics, transport modulation and ligand recognition. A detailed functional characterization of transporters would provide opportunities to develop new compounds targeting these key drug targets. Here, we are giving an overview of two major human LeuT-fold families, SLC6 and SLC7, with an emphasis on the most relevant members of each family for drug development. We gather the most recent understanding on the structural determinants of selectivity within and across the two families. We then use this information to discuss the benefits of a more generalized structural and functional annotation of the LeuT fold and the implications of such mapping for drug discovery.

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Section: Introductionmentioning

confidence: 99%

Toward a Systematic Structural and Functional Annotation of Solute Carriers Transporters—Example of the SLC6 and SLC7 Families

Colas

2020

Front. Pharmacol.

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“…Solute Carriers (SLCs) represent the largest family of human transporter proteins, consisting of more than 400 members 1,2 . Despite the importance of these proteins in determining metabolic states and adaptation to environmental changes, a large proportion of them is still orphan and lacks associated substrates 1,3,4 . Here we describe a systematic Transmembrane transporters are key contributors to the energetic and metabolic needs of a cell.…”

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confidence: 99%

“…Further studies employing higher-order genetics 10,11,39 or modifications of media composition 40 can be expected to reveal further dependencies among this class of genes. As the functional breadth of SLCs and their potential as a target class becomes increasingly recognized 1,4 , systematic approaches such as the genetic interaction map described here will be necessary to define functions and therapeutically relevant applications of Solute Carriers. Mapping genetic interactions in human cells promises to be a very powerful approach to assign gene products to core biochemical and cellular functions.…”

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confidence: 99%

A systematic genetic interaction map of human solute carriers assigns a role to SLC25A51/MCART1 in mitochondrial NAD uptake

Gottardi

Fiume

Goldmann

et al. 2020

Preprint

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Solute Carriers (SLCs) represent the largest family of human transporter proteins, consisting of more than 400 members1,2. Despite the importance of these proteins in determining metabolic states and adaptation to environmental changes, a large proportion of them is still orphan and lacks associated substrates1,3,4. Here we describe a systematic mapping of genetic interactions among SLCs in human cells. Network-based identification of correlated genetic interaction profile neighborhoods resulted in initial functional assignments to dozens of previously uncharacterized SLCs. Focused validation identified SLC25A51/MCART1 as the SLC enabling mitochondrial import of NAD(H). This functional interaction map of the human transportome offers a route for systematic integration of transporter function with metabolism and provides a blueprint for elucidation of the dark genome by biochemical and functional categories.

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“…There are increasing efforts to uncover the biological roles of SLC transporters using a multitude of new methodologies, including various in vitro model systems, transgenic animals, human genetic studies, and combinations of experimental and computational approaches. 4 For example, in recent studies, in vitro metabolomic screens have been used to identify the endogenous substrates of SLC22A1 (OCT1), which was previously thought to function primarily as a xenobiotic transporter. 5 Metabolomic GWAS were used to reveal important endogenous substrates of SLCO1B1 (OATP1B1), an important transporter in hepatic drug disposition.…”

Section: Introductionmentioning

confidence: 99%

Deorphaning a solute carrier 22 family member, SLC22A15, through functional genomic studies

et al. 2020

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hydroxyethyl)-1piperazineethanesulfonic acid); IC 50 , concentration of a compound to inhibit half of the activity; Km, the concentration of substrates to reach half of the maximum uptake rate (Vmax); MPP + , 1-methyl-4-phenylpyridinium; OAT, organic anion transporter; OCT, organic cation transporter; OCTN, organic zwitterions/cation transporter; PEPT, peptide transporter; SLC, solute carrier; SLCO, solute carrier family of organic anion transporting polypeptides; SNP, single-nucleotide polymorphism.

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The RESOLUTE consortium: unlocking SLC transporters for drug discovery

Cited by 78 publications

References 5 publications

Toward a Systematic Structural and Functional Annotation of Solute Carriers Transporters—Example of the SLC6 and SLC7 Families

Toward a Systematic Structural and Functional Annotation of Solute Carriers Transporters—Example of the SLC6 and SLC7 Families

A systematic genetic interaction map of human solute carriers assigns a role to SLC25A51/MCART1 in mitochondrial NAD uptake

Deorphaning a solute carrier 22 family member, SLC22A15, through functional genomic studies

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