Science
March 21, 2013
Daniel Wacker, Chong Wang, Vsevolod Katritch et al.
689 citations
Serotonin receptors are targets for drugs treating depression, obesity, and migraine headaches. Crystal structures of two serotonin receptor subtypes bound to antimigraine medications or a precursor of LSD reveal how subtle differences in ligand binding cause substantial differences in receptor signaling and biological responses. The structures show that the same ligand can activate one or both of the two main serotonin receptor signaling mechanisms, depending on which receptor it binds.
Science
March 22, 2013
Chong Wang, Yi Jiang, Jinming Ma et al.
522 citations
Two research teams independently determined the crystal structures of two serotonin receptors bound to antimigraine drugs or a precursor of LSD. The structures show that subtle differences in how ligands bind to these receptors lead to substantial differences in the signals generated and the resulting biological responses. The same ligand can activate one or both of the two main serotonin receptor signaling mechanisms, depending on which specific receptor it binds to.
Cell
January 26, 2017
Daniel Wacker, Sheng Wang, J. Mccorvy et al.
466 citations
The hallucinogen LSD binds to the human serotonin receptor 5-HT2B, and its crystal structure reveals conformational rearrangements that accommodate LSD, explaining the selectivity of its diethylamide group. LSD dissociates very slowly from both 5-HT2BR and 5-HT2AR, a key receptor for its psychoactive effects. Molecular dynamics simulations suggest that a 'lid' formed by extracellular loop 2 (EL2) at the binding pocket entrance may cause LSD's slow binding kinetics. A mutation that increases this lid's mobility greatly speeds up LSD's binding and selectively reduces LSD-mediated β-arrestin2 recruitment, providing a molecular explanation for LSD's actions at human serotonin receptors.
Nature
June 1, 2024
Audrey L Warren, David Lankri, Michael J Cunningham et al.
74 citations
Psychedelic substances like LSD and psilocybin show potential for treating neuropsychiatric disorders, primarily acting through the serotonin 5-HT2A receptor. However, 5-HT1A also contributes to the effects of tryptamine hallucinogens, especially 5-MeO-DMT from Colorado River toad toxin. Using cryo-EM structures, medicinal chemistry, and mouse behavior, researchers mapped how 5-MeO-DMT engages 5-HT1A. They characterized molecular determinants of signaling potency, efficacy, and selectivity at both 5-HT1A and 5-HT2A. A 5-HT1A-selective analogue of 5-MeO-DMT lacked hallucinogenic effects but retained anxiolytic-like and antidepressant-like activity in socially defeated animals, uncovering molecular aspects that may aid developing new neuropsychiatric medications.
The Journal of biological chemistry
September 1, 2023
Omar B Sanchez-Reyes, Gregory Zilberg, John D McCorvy et al.
10 citations
Opioids, cannabinoids, and psychedelics all act by binding to G protein-coupled receptors (GPCRs), which mediate their inebriating, lethal, and therapeutic effects. Recent structural studies reveal the molecular mechanisms of drugs like fentanyl, tetrahydrocannabinol, and lysergic acid diethylamide at their respective GPCR subtypes. These insights facilitate drug discovery, both for developing treatments to combat substance abuse and for harnessing the therapeutic potential of certain drugs.
UNC Libraries
June 7, 2024
Kami Kim, T Che, Ouliana Panova et al.
Psychedelics such as LSD, psilocybin, and related compounds are used recreationally and are being investigated as treatments for depression, anxiety, and substance abuse. Their therapeutic and hallucinogenic effects depend on activating the 5-HT2A serotonin receptor, but the molecular details were unclear. Using cryo-electron microscopy and X-ray crystallography, researchers determined the structures of the 5-HT2A receptor bound to a hallucinogen, LSD, and an inverse agonist. These structures reveal how the receptor interacts with Gαq protein and changes shape when activated. The findings may guide development of more selective drugs for neuropsychiatric disorders.