A Competitive Inhibitor Traps LeuT in an Open-to-Out Conformation

Journal Article · Tue Jan 01 00:00:00 EST 2008 · Science

DOI:https://doi.org/10.1126/science.1166777· OSTI ID:979973

Singh, S; Piscitelli, C; Yamashita, A; Gouaux, E

Secondary transporters are workhorses of cellular membranes, catalyzing the movement of small molecules and ions across the bilayer and coupling substrate passage to ion gradients. However, the conformational changes that accompany substrate transport, the mechanism by which a substrate moves through the transporter, and principles of competitive inhibition remain unclear. We used crystallographic and functional studies on the leucine transporter (LeuT), a model for neurotransmitter sodium symporters, to show that various amino acid substrates induce the same occluded conformational state and that a competitive inhibitor, tryptophan (Trp), traps LeuT in an open-to-out conformation. In the Trp complex, the extracellular gate residues arginine 30 and aspartic acid 404 define a second weak binding site for substrates or inhibitors as they permeate from the extracellular solution to the primary substrate site, which demonstrates how residues that participate in gating also mediate permeation.

• Research Organization: Brookhaven National Lab. (BNL), Upton, NY (United States). National Synchrotron Light Source
• Sponsoring Organization: Doe - Office Of Science
• DOE Contract Number: DE-AC02-98CH10886
• OSTI ID: 979973
• Report Number(s): BNL-92891-2010-JA; SCEHDK; TRN: US201015%%1358
• Journal Information: Science, Vol. 322; ISSN 0193-4511
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE
AMINO ACIDS
ARGININE
ASPARTIC ACID
CONFORMATIONAL CHANGES
COUPLING
FUNCTIONALS
INHIBITION
IONS
LEUCINE
MEMBRANES
MOLECULES
RESIDUES
SODIUM
SOLUTIONS
SUBSTRATES
TRANSPORT
TRAPS
TRYPTOPHAN
national synchrotron light source