5-HT 2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology

Journal: Cell

Published: 2018-02-08

DOI: 10.1016/j.cell.2018.01.001

Affiliations: 13

Authors: 20

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Research Highlight

The path to more intelligent drug design

© Stocktrek Images/Getty

© Stocktrek Images/Getty

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.

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  1. Cell 172, 719–730 (2018). doi: 10.1016/j.cell.2018.01.001
Institutions Share
iHuman Institute, ShanghaiTech, China 0.27
UNC Department of Pharmacology, United States of America (USA) 0.23
Department of Drug Design and Pharmacology, UCPH, Denmark 0.18
EPFL Laboratory of Physical Chemistry of Polymers and Membranes (LCPPM), Switzerland 0.05
School of Life Science and Technology (SLST), ShanghaiTech, China 0.05
National Laboratory of Biomacromolecules (NLB), IBP CAS, China 0.04
USC Department of Biological Sciences, United States of America (USA) 0.03
USC Department of Chemistry, United States of America (USA) 0.03
USC Bridge Institute, United States of America (USA) 0.03
USC Michelson Center for Convergent Bioscience, United States of America (USA) 0.03
NIMH Psychoactive Drug Screening Program (PDSP), United States of America (USA) 0.03
Moscow Institute of Physics and Technology - State University (MIPT), Russia 0.02
Key Laboratory of Stem Cell and Regenerative Medicine, KMU, China 0.02