Structures of multidrug and toxic compound extrusion transporters and their mechanistic implications.
Multidrug resistance poses grand challenges to the effective treatment of infectious diseases and cancers. Integral membrane proteins from the multidrug and toxic compound extrusion (MATE) family contribute to multidrug resistance by exporting a wide variety of therapeutic drugs across cell membranes. MATE proteins are conserved from bacteria to humans and can be categorized into the NorM, DinF and eukaryotic subfamilies. MATE transporters hold great appeal as potential therapeutic targets for curbing multidrug resistance, yet their transport mechanism remains elusive. During the past 5 years, X-ray structures of 4 NorM and DinF transporters have been reported and guided biochemical studies to reveal how MATE transporters extrude different drugs. Such advances, although substantial, have yet to be discussed collectively. Herein I review these structures and the unprecedented mechanistic insights that have been garnered from those structure-inspired studies, as well as lay out the outstanding questions that present exciting opportunities for future work.
a Department of Biochemistry & Molecular Biology , Rosalind Franklin University of Medicine & Science , Chicago , IL , USA.
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D000595:Amino Acid Sequence; D000890:Anti-Infective Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017920:Antiporters / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D003141:Communicable Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017124:Conserved Sequence; D018432:Drug Resistance, Multiple / Q000235:genetics*; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D019450:Genes, MDR; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D027701:Organic Cation Transport Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000072417:Protein Domains; D017433:Protein Structure, Secondary; D016415:Sequence Alignment
D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D017920:Antiporters; D001426:Bacterial Proteins; C574042:DinF protein, E coli; D029968:Escherichia coli Proteins; C114619:NorM protein, bacteria; D027701:Organic Cation Transport Proteins
cation binding; membrane transporter; multidrug efflux inhibitor; multidrug resistance; substrate recognition