Tryptophan Clarifies Antidepressant Drug Binding | December 15, 2008 Issue - Vol. 86 Issue 50 | Chemical & Engineering News
Volume 86 Issue 50 | p. 30 | Concentrates
Issue Date: December 15, 2008

Tryptophan Clarifies Antidepressant Drug Binding

An X-ray structure indicates an alternative starting point for designing new drugs
Department: Science & Technology
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Tryptophan (green molecule, center) acts as a strut for the bacterialtransporter LeuT, buttressing its open conformation.
Credit: Courtesy of Chayne Piscitelli
8650scicon_fig3LeuT
 
Tryptophan (green molecule, center) acts as a strut for the bacterialtransporter LeuT, buttressing its open conformation.
Credit: Courtesy of Chayne Piscitelli

A newly captured atomic-level view of a propped-open bacterial protein could aid antidepressant drug design, according to a report by Eric Gouaux of Oregon Health & Science University and colleagues (Science 2008, 322, 1655). Most antidepressants work by blocking neurotransmitter reuptake, a task the drug molecules accomplish by binding to human neurotransmitter transporter proteins such as the serotonin transporter. In transporter structures obtained of this family to date, the substrate molecule is occluded (C&EN, Aug. 13, 2007, page 14), leaving the mechanism by which drugs and substrates enter the protein a mystery. Now, Gouaux and colleagues have trapped a bacterial transporter called LeuT in a new pose, open to the outside environment. In the team's X-ray structure, LeuT interacts with a tryptophan molecule that occupies the substrate-binding site, and the amino acid's large side chain braces the binding pocket open. The new structure is likely "a more realistic model for the form of the transporter to which drugs bind" and could be an excellent starting point for designing improved therapeutics, Gary Rudnick of Yale University School of Medicine says.

 
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