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Proc Natl Acad Sci U S A. 2019 Feb 5;116(6):2086-2090. doi: 10.1073/pnas.1806206116. Epub 2019 Jan 18.

Structural basis for substrate binding and specificity of a sodium-alanine symporter AgcS.

Author information

1
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147.
2
Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095.
3
Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
4
Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
5
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147; tgonen@ucla.edu.

Abstract

The amino acid, polyamine, and organocation (APC) superfamily is the second largest superfamily of membrane proteins forming secondary transporters that move a range of organic molecules across the cell membrane. Each transporter in the APC superfamily is specific for a unique subset of substrates, even if they possess a similar structural fold. The mechanism of substrate selectivity remains, by and large, elusive. Here, we report two crystal structures of an APC member from Methanococcus maripaludis, the alanine or glycine:cation symporter (AgcS), with l- or d-alanine bound. Structural analysis combined with site-directed mutagenesis and functional studies inform on substrate binding, specificity, and modulation of the AgcS family and reveal key structural features that allow this transporter to accommodate glycine and alanine while excluding all other amino acids. Mutation of key residues in the substrate binding site expand the selectivity to include valine and leucine. These studies provide initial insights into substrate selectivity in AgcS symporters.

KEYWORDS:

crystal structure; membrane protein; secondary transporter; specificity; substrate binding

PMID:
30659158
PMCID:
PMC6369739
[Available on 2019-08-05]
DOI:
10.1073/pnas.1806206116
[Indexed for MEDLINE]

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