a death receptor crystal structure

Illustrations of the binding pockets of 5-HT1B and 5-HT2b Serotonin receptors. Image from Science via C&EN.

Receptors for the neurotransmitter serotonin are popular drug targets. Drugs that target these receptors are used to treat problems like depression and migraine headaches. Serotonin receptors are also the targets of some psychedelic drugs like LSD and mescaline.

There are at least 14 subtypes of serotonin receptors known. Most of the drugs that target one subtype of serotonin receptor will also target the others. This is usually not a problem except in the case of one type called 5-HT2B. This receptor is called the death receptor because activating it can cause heart problems that will lead to death. This receptor is to be avoided.

Chemical & Engineering News brings word of two crystal structures that might help drug developers better avoid activating the 5-HT2B subtype of receptors:

Help will come from new crystal structures of 5-HT1B and of 5-HT2B, each bound to the migraine drugs ergotamine and dihydroergotamine (Science,DOI: 10.1126/science.1232807 and DOI: 10.1126/science.1232808). The findings provide a blueprint for designing more selective 5-HT inhibitors.

The team behind the structures includes Raymond C. Stevens, a chemistry and molecular biology professor at Scripps Research Institute, La Jolla, Calif.; Bryan L. Roth, a pharmacology professor at the University of North Carolina; H. Eric Xu, director of the Center for Structural Biology & Drug Discovery at Van Andel Research Institute in Grand Rapids, Mich., and Hualiang Jiang, a professor at the Shanghai Institute of Materia Medica.

This is major news for our field,” adds Kathryn A. Cunningham, a professor in the pharmacology and toxicology department at the University of Texas Medical Branch. “The structures were solved for the receptor-ligand cocrystals, which provides important insights into how the receptors work.”

The importance of selectivity was most infamously illustrated in the 1990s by the obesity treatment Fen-Phen (fenfluramine-phentermine). Both molecules targeted 5-HT receptors, but they weren’t selective enough. Unbeknown to scientists, they also bound to the death receptor, 5-HT2B, triggering sometimes-fatal cardiovascular side-effects. Fen-Phen’s withdrawal from the market was the largest in history and cost its manufacturer, Wyeth, billions of dollars in damages.

Check out the original research here and here.