Serotonin Receptors Can Shape Drug Effects from LSD to Migraine Medication

A team has determined and analyzed the high-resolution atomic structures of two kinds of human serotonin receptor, findings that shed light on several drugs' complex and sometimes harmful effects. 

Credit: Photo courtesy of The Scripps Research Institute.

A team including scientists from The Scripps Research Institute (TSRI), the University of North Carolina at Chapel Hill and the Chinese Academy of Sciences has determined and analyzed the high-resolution atomic structures of two kinds of human serotonin receptor.

The new findings help explain why some drugs that interact with these receptors have had unexpectedly complex and sometimes harmful effects.

"Understanding the structure-function of these receptors allows us to discover new biology of serotonin signaling and also gives us better ideas about what biological questions to probe in a more intelligent manner," said TSRI Professor Raymond Stevens, who was a senior investigator for the new research.

The studies were published in two papers on March 21, 2013 in Science Express, the advance online version of the journal Science.

Pioneering Important Molecular Structures
Stevens's laboratory at TSRI has pioneered the development of techniques for determining the 3D atomic structures of cellular receptors -- particularly the large receptor class known as G protein-coupled receptors (GPCRs).

GPCRs sit in the cell membrane and sense various molecules outside cells. When certain molecules bind to them, the receptor's respond in a way to transmit a signal inside the cell.

"Because G protein-coupled receptors are the targets of nearly 50 percent of medicines, they are the focus of several major National Institutes of Health (NIH) initiatives," said Jean Chin of the NIH's National Institute of General Medical Sciences, which partly funded the work through the Protein Structure Initiative.

"These detailed molecular structures of two serotonin receptor subfamilies bound to antimigraines, antipsychotics, antidepressants or appetite suppressants will help us understand how normal cellular signaling is affected by these drugs and will offer a valuable framework for designing safer and more effective medicines."

Serotonin receptors are no less important. "Nearly all psychiatric drugs affect serotonin receptors to some extent, and these receptors also mediate a host of effects outside the brain, for example on blood coagulation, smooth muscle contraction and heart valve growth," said Bryan Roth, a collaborator on both studies who is professor of pharmacology at the University of North Carolina (UNC).

Untangling Two Serotonin Receptors
Roth's laboratory teamed up with Stevens's as part of the National Institute of General Medical Sciences (NIGMS) Protein Structure Initiative.

For this project the two labs also worked with the laboratories of Professors Eric Xu and Hualiang Jiang at the Shanghai Institute of Materia Medica, part of the Chinese Academy of Sciences.

"By collaborating with the Chinese teams we were able to complete a much more thorough study and get the most out of our fundamental structural results," said Stevens.

In the first of the new studies, co-lead author Chong Wang, a graduate student in the Stevens laboratory, and his colleagues determined the structure of the serotonin receptor subtype 5-HT1B, the principal target of several drug classes. (5-HT, or 5-hydroxytryptamine, is a technical term for serotonin.)

The team produced the 5-HT1B receptor while it was bound by either ergotamine or dihydroergotamine -- two old-line anti-migraine drugs that work in part by activating 5-HT1B receptors.

With the help of the special fusion protein, nicknamed BRIL (apocytochrome b562RIL), Wang and colleagues were able to stabilize these structures and coax them to line up in a regular ordering known as a crystal.

X-ray crystallography revealed, at high resolution, an atomic structure of 5-HT1B with a main binding pocket and a separate, extended binding pocket.

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