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The field of substrate transport systems has grown steadily over the past decade and is now considered important for developing treatments to diseases. Human solute carriers (SLCs) consist of more than 420 different transporters, organized into 65 families (http://slc.bioparadigms.org/) according to sequence homology and transport functions. SLCs mediate the movement of ions, drugs, and metabolites across cell membranes, and dysfunction is associated with various diseases such as diabetes, cancer, and central nervous system (CNS) disorders. Thus, SLCs are emerging as important targets for therapeutic intervention and drug discovery. Despite their importance, sequence and structural information on SLCs is lacking, but recent biochemical and computational advances have expanded our understanding of SLC pharmacology. In particular, structures of SLCs elucidated by X-ray crystallography and cryo-electron microscopy (EM) have facilitated structure-based ligand prediction, comparison and modeling of SLC transporters, and virtual screening of small molecule libraries. Most available SLC structures are from prokaryotes, all SLC structures are classified into four major groups based on protein fold, and major facilitator superfamily (MFS) and leucine transporters (LeuT) have received most attention. This review systematically analyses the structures of different SLCs, and their molecular mechanisms of action and substrate recognition. Understanding drug-transporter interactions at the molecular level is essential for designing drugs with optimal therapeutic effects. Finally, we summarize the latest research trends, applications and computational approaches to developing solutes selectivity and inhibitors, including modelling techniques focused on the structure-based drug design for human SLC transporters.
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참고문헌 (182)
참고문헌 신청
Abramson, J. / 2009 / Structure and function of Na(+)-symporters with inverted repeats / Curr Opin Struct Biol 19:425~432
Alakbarzade, V. / 2015 / A partially inactivating mutation in the sodium-dependent lysophosphatidylcholine transporter MFSD2A causes a non-lethal microcephaly syndrome / Nat Genet 47:814~817
Alper, S. L. / 2013 / The SLC26 gene family of anion transporters and channels / Mol Aspects Med 34:494~515
Andersen, J. / 2009 / Recent advances in the understanding of the interaction of antidepressant drugs with serotonin and norepinephrine transporters / Chem Commun 7:3677~3692
Anderson, C. M. / 2013 / SLC27 fatty acid transport proteins / Mol Aspects Med 34:516~528
Alakbarzade, V. / 2015 / A partially inactivating mutation in the sodium-dependent lysophosphatidylcholine transporter MFSD2A causes a non-lethal microcephaly syndrome / Nat Genet 47:814~817
Alper, S. L. / 2013 / The SLC26 gene family of anion transporters and channels / Mol Aspects Med 34:494~515
Andersen, J. / 2009 / Recent advances in the understanding of the interaction of antidepressant drugs with serotonin and norepinephrine transporters / Chem Commun 7:3677~3692
Anderson, C. M. / 2013 / SLC27 fatty acid transport proteins / Mol Aspects Med 34:516~528
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