Targeting Solute Carrier Transporters through Functional Mapping

Solute carrier (SLC) transporters are emerging drug targets. Identifying the molecular determinants responsible for their specific and selective transport activities describing key interactions with ligands crucial steps towards design of potential new drugs. A general functional mapping across more than 400 human SLC would pave way to rational systematic molecules modulating cellular transport. mediate a broad range solutes, such as ions, nutrients, metabolites biological membranes. In human, dysregulation homeostasis transported substrates, has been associated multiple diseases disorders, cancers. Additionally, SLCs play an essential role in absorption, distribution, metabolism, elimination, therapeutic Thus, targets [1.Lin L. et al.SLC targets: opportunities.Nat. Rev. Drug Discov. 2015; 14: 543-560Crossref PubMed Scopus (330) Google Scholar,2.Wang W.W. al.The druggability solute carriers.J. Med. Chem. 2020; 6: 3834-3867Crossref (21) Scholar], that remained understudied until recently [3.Cesar-Razquin A. al.A call research on carriers.Cell. 162: 478-487Abstract Full Text PDF (293) Scholar]. Understanding these complex systems requires description many aspects functioning (e.g., protein partners, conformational changes kinetics transport, response cofactors, differential expression different cell types). These can be probed by various technologies, including structural determination, genetic editing, metabolomics, animal models, chemical biology, basic biochemistry, etc. Among them, structure-based techniques commonly used improve our understanding substrate specificity determinants. As such, they bear great guide prospective Importantly, methods most powerful when integrating experimental information together data generated silico [4.Rout M.P. Sali Principles integrative biology studies.Cell. 2019; 177: 1384-1403Abstract (93) Scholar,5.Schlessinger al.Molecular modeling drug-transporter interactions-an international transporter consortium perspective.Clin. Pharmacol. Ther. 2018; 10: 818-835Crossref (25) The determination 3D structures is challenging due inherent difficulty expressing purifying membrane proteins native state. result, about 100 have resolved this day, represent only 25 unique proteins. Fortunately, several prokaryotic homologs available, good templates build homology models [6.Colas C. Transporters: structure, function, discovery.MedChemComm. 2016; 7: 1069-1081Crossref postulated describe intermediate states cycle, thus improving process, providing opportunities conformation modulators. mechanism essence dynamic process. According alternating access paradigm, needs go from outward, inward conformation, passing through occluded state, where isolated within binding site. This local gating movements well global two domains respect each other. Three distinct folds predominately described, them (Figure 1A ) [7.Drew D. Boudker O. Shared mechanisms transporters.Annu. Biochem. 85: 543-572Crossref (208) Scholar]: (i) rocker-switch corresponds fold transporting, example, di/tri-peptide [peptide 1 (PepT1), SLC15A1], or glucose [glucose (GLUT1), SLC2A1]. (ii) gated-pore rocking bundle adopted instance, neutral amino acid [(LAT1), SLC7A5], serotonin [(SERT), SLC6A4]. (iii) elevator operated among others glutamate [excitatory (EAAT1)]. comprised transmembrane ?-helices (usually 10–14), regrouped into pseudo-repeats related symmetry axis 1B). Plenty efforts made determinants, defining important SLCs. For basis creatine [(CreaT), SLC6A8], exerts its substrates using [8.Colas al.Studies (CreaT, SLC6A8) models.Sci. Rep. 6241Crossref (4) described. CreaT belongs SLC6 family operates via mechanism. It pharmacologically relevant target, it intracellular uptake creatine, metabolite regulating ATP tissues high-energy demand. Briefly, shown potent inhibitors exhibit 4.5 Å long carbon linker between guanidine carboxylate moieties, maintain optimal deprotonated cysteine (C144) transporter, glycine (G71), conserved ?-aminobutyric (GABA) subgroup 1C). Such features site complemented ligand’s scaffolds, confer very properties not found other members family. Despite similar findings reported SLCs, we still far complete how select substrates. particular, one third called ‘orphans’ do any known nor function [9.Perland E. Fredriksson R. Classification secondary active transporters.Trends Sci. 2017; 38: 305-315Abstract (97) 456 grouped 65 families based sequence similarities. characteristic property ‘superfamily’ high variability. Many share weak similarities, sometimes even if adopt same [10.Schlessinger al.Comparison carriers.Protein 2010; 19: 412-428Crossref (75) While evolutionary origin main dated prior divergence bilaterian species, large number genes seem evolved rapidly species- lineage-specific [11.Hoglund P.J. remarkably history majority present before Bilaterian species.Mol. Biol. Evol. 2011; 28: 1531-1541Crossref (108) Moreover, existence three involvement suggest independent scenarios, leading dynamical solutions performing function. Interestingly, while some unrelated may belonging raises issue detection signals data. Evolutionary conservation widely recognized proxy Residues under strong pressure expected roles folding activity. More variable residues also ensuring maintaining optimizing certain over To identify residues, necessary account inter-dependencies compensatory mutations) group sequences according [12.Laine al.GEMME: simple fast epistatic model predicting mutational effects.Mol. 36: 2604-2619Crossref (8) was illustrated G protein-coupled receptor (GPCR) superfamily, selectivity signatures could identified receptors coupling [13.Flock T. al.Selectivity GPCR-G-protein binding.Nature. 545: 317-322Crossref (182) case transporters, deciphering complexity multiplicity events present-day challenging. calls development computational approaches exploiting both sequence- information. Specifically, similarities observed many, highly divergent advantageously establish holistic positions 2). striking commonalities so far, few connections established families. Of particular interest medicinal chemistry allosteric mechanisms, which molecule at distant ligand (orthosteric) site, modulates transporter. described processes [14.Canul-Tec J.C. al.Structure inhibition excitatory 1.Nature. 544: 446-451Crossref (119) Scholar, 15.Coleman J.A. Gouaux Structural recognition diverse antidepressants transporter.Nat. Struct. Mol. 25: 170-175Crossref (66) 16.Kortagere S. al.Identification novel modulators EAAT2.ACS Neurosci. 9: 522-534Crossref (26) 17.Plenge P. high-affinity inhibitor Commun. 11: 1491Crossref (13) Scholar] suggested rocker switch [18.Quistgaard E.M. al.Understanding major facilitator superfamily (MFS): way.Nat. Cell 17: 123-132Crossref (192) specifically, EAAT1 (SLC1A3) SERT (SLC6A4) [15.Coleman Scholar,17.Plenge cases, bind interface scaffold mobile domains, hence preventing change. activator revealed EAAT2 (SLC1A2) [16.Kortagere ‘unlock’ states, increased rate GPCRs, designing proven efficient strategy, target subtypes selectively orthosteric ligands. results show clinical developing transporters. New then used: tools allostery concept transporters; hits optimization. generally, hypothesized possible systematically transfer annotations [19.Colas Toward systematic, structural, annotation carriers transporters—example SLC7 families.Front. 1229Crossref (2) provide concepts tackle discovery Several layers, gradual increase precision, envisioned. first reveal regulatory shared all regulation interface). second specific, detailed modulations literature polarity, protonation, shape allosteric). uncover transporting family-specific ‘signatures’, residue resolution Notably, layers thought complementary, integrate structure sequence-based approaches. Collecting state-of-the-art structure–function relationships manner, step shall help strategies, specifically control activity pharmacological Here propose actions taken achieving goal. First, believed learning best-studied insights efficiently examples GPCRs inspire provided here. Second, strongly connecting sharing (despite families) essential. article pointing out fold-dependent modulation. Third, combining analysis, considerably identification level, functions. Similarly sites LeuT-fold will throughout entire involved nonconserved specificity, sites. permit targeting manner. Finally, proposed constitute method, building map Ultimately, comprehensive approach applied beyond characterizing regulation, better understand work acknowledges funding Innovative Medicines Initiative 2 Joint Undertaking grant agreement No. 777372 (‘RESOLUTE’). receives support European Union’s Horizon 2020 innovation program EFPIA.