RT Journal Article SR Electronic T1 A Comprehensive Structure-Based Alignment of Prokaryotic and Eukaryotic Neurotransmitter/Na+ Symporters (NSS) Aids in the Use of the LeuT Structure to Probe NSS Structure and Function JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 1630 OP 1642 DO 10.1124/mol.106.026120 VO 70 IS 5 A1 Thijs Beuming A1 Lei Shi A1 Jonathan A. Javitch A1 Harel Weinstein YR 2006 UL http://molpharm.aspetjournals.org/content/70/5/1630.abstract AB The recently elucidated crystal structure of a prokaryotic member of the neurotransmitter/sodium symporter (NSS) family (Yamashita et al., 2005) is a major advance toward understanding structure-function relationships in this important class of transporters. To aid in the generalization of these results, we present here a comprehensive sequence alignment of all known prokaryotic and eukaryotic NSS proteins, based on the crystal structure of the leucine transporter from Aquifex aeolicus (LeuT). Regions of low sequence identity between prokaryotic and eukaryotic transporters were aligned with the aid of a number of bioinformatics tools, and the resulting alignments were validated by comparison with experimental data. In a number of regions, including the transmembrane segments 4, 5, and 9 as well as extracellular loops 2, 3, and 4, our alignment differs from the one proposed previously [Nature (Lond)437: 215-223, 2005]. Important similarities and differences among the sequences of NSS proteins in regions likely to determine selectivity in substrate binding and mechanisms of transport regulation are discussed in the context of the LeuT structure and the alignment. The American Society for Pharmacology and Experimental Therapeutics