5-HT 2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology
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A ShanghaiTech University-led team has revealed the structures of a serotonin receptor when bound to a polypharmacologic drug—one that binds to many receptors—and when bound to a selective drug. In doing so, they elucidated multiple receptor properties that may enable more intelligent drug design.
The team imaged a specific class of serotonin receptor, known as a 5-HT2c receptor, when bound to the polypharmacologic biomolecule ergotamine. By comparing the complex’s structure to other known ergotamine-complementary receptors, the researchers identified ten points of interaction that are highly conserved across many receptors and facilitate ergotamine binding.
In contrast, the drug ritanserin is selective towards the 5-HT2 family of serotonin receptors and, on examination, revealed a binding profile not found outside of the family.
The different changes induced in 5-HT2c by ergotamine and ritanserin indicate distinct signaling mechanisms that may inform future efforts into pathway-specific drugs.
- Cell 172, 719–730 (2018). doi: 10.1016/j.cell.2018.01.001