Molecular modeling of PepT1--towards a structure.
The proton-coupled uptake of di- and tri-peptides is the major route of dietary nitrogen absorption in the intestine and of reabsorption of filtered protein in the kidney. In addition, the transporters involved, PepT1 (SLC15a1) and PepT2 (SLC15a2), are responsible for the uptake and tissue distribution of a wide range of pharmaceutically important compounds, including beta-lactam antibiotics, angiotensin-converting enzyme inhibitors, anti-cancer and anti-viral drugs. PepT1 and PepT2 are large proteins, with over 700 amino acids, and to date there are no reports of their crystal structures, nor of those of related proteins from lower organisms. Therefore there is virtually no information about the protein 3-D structure, although computer-based approaches have been used to both model the transmembrane domain (TM) layout and to produce a substrate binding template. These models will be discussed, and a new one proposed from homology modeling rabbit PepT1 to the recently crystallized bacterial transporters LacY and GlpT. Understanding the mechanism by which PepT1 and PepT2 bind and transport their substrates is of great interest to researchers, both in academia and in the pharmaceutical industries.
Meredith
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Department of Physiology, Anatomy & Genetics, Le Gros Clark Building, University of Oxford, South Parks Road, Oxford, OX1 3QX, UK. david.meredith@anat.ox.ac.uk
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D000595:Amino Acid Sequence; D000818:Animals; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000235:genetics; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D026901:Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009004:Monosaccharide Transport Proteins / Q000737:chemistry / Q000235:genetics; D009154:Mutation; D000074011:Peptide Transporter 1; D017434:Protein Structure, Tertiary; D011817:Rabbits; D017386:Sequence Homology, Amino Acid; D027981:Symporters / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D029968:Escherichia coli Proteins; C488962:GlpT protein, E coli; C050221:LacY protein, E coli; D026901:Membrane Transport Proteins; D009004:Monosaccharide Transport Proteins; D000074011:Peptide Transporter 1; C082186:SLC15A1 protein, human; D027981:Symporters; C093694:hydrogen-coupled oligopeptide transporter PepT2