Neuron
October 5, 2022
Can Cao, Ximena Barros-Álvarez, Shicheng Zhang et al.
158 citations
Lysergic acid diethylamide (LSD) acts through serotonin 5-HT2-family receptors, primarily 5-HT2A, but the closely related 5-HT2B receptor serves as a model due to its high expression. Cryo-electron microscopy structures of LSD-bound 5-HT2B in three states—transducer-free, coupled with Gq protein, and coupled with β-arrestin-1—reveal distinct signaling snapshots from a partially active to fully active states. These findings provide comprehensive molecular insights into LSD's signaling mechanisms and may accelerate the discovery of novel psychedelic drugs.
Nature
May 1, 2023
Jianming Han, Jingying Zhang, Antonina L. Nazarova et al.
79 citations
Treatments for pain or addiction targeting the κ-opioid receptor often cause hallucinogenic side effects. To understand this, cryo-electron microscopy mapped the receptor's structure with various G-proteins and compounds. These detailed maps uncovered molecular controls for G-protein binding and drug selectivity, showing distinct preferences. This clarifies opioid action, establishing a foundation for developing safer, pathway-selective therapies.
Cell Reports
August 1, 2022
Ryan H. Gumpper, Jonathan F. Fay, Bryan L. Roth
49 citations
The serotonin 2C receptor, a G protein-coupled receptor (GPCR) targeted by drugs like the weight-loss medication lorcaserin and the psychedelic psilocin, exists in many protein isoforms due to RNA editing. This study presents the structures of three representative isoforms bound to each drug and analyzes agonist activation and constitutive activity across all 24 isoforms. A unique hydrogen-bonding network on intracellular loop 2, which is altered by RNA editing, differentially affects the receptor's constitutive and agonist signaling activities.
Neuron
July 15, 2025
Manish K. Jain, Ryan H. Gumpper, Samuel T. Slocum et al.
42 citations
Classical psychedelics like LSD, psilocybin, and mescaline produce their mind-altering effects by activating the 5-HT2A serotonin receptor. Recent clinical studies indicate they may also help treat depression, anxiety, migraines, cluster headaches, drug abuse, and PTSD. This work examined 41 psychedelics from three chemical classes, testing them against 318 human G-protein-coupled receptors and, for LSD, over 450 human kinases. The compounds potently activated nearly every serotonin, dopamine, and adrenergic receptor. They also stimulated multiple signaling pathways through the 5-HT2A receptor, each linked to psychedelic-like effects in animals. The findings suggest that many molecular targets contribute to the overall actions of psychedelics.
Nat Commun
March 19, 2025
Ryan H. Gumpper, Manish K. Jain, Kuglae Kim et al.
31 citations
Classical psychedelics are being studied for treating depression, addiction, anxiety, and cluster headaches. Their therapeutic effects are thought to involve the 5-HT2A serotonin receptor. Seven cryo-EM structures were determined, covering major classes of psychedelic and non-psychedelic agonists, including a β-arrestin-biased compound. These structures reveal both common and distinct molecular interactions between different psychedelics and the receptor. The findings provide a mechanistic understanding of 5-HT2A activation that could aid development of new drugs with fewer side effects.
Nature Structural & Molecular Biology
June 22, 2026
Qianru Jiang, Jianming Han, Eve Fine et al.
Ketamine, used for treatment-resistant depression and severe pain, acts primarily by blocking the N-methyl-D-aspartate receptor, but its therapeutic and abuse-related effects may involve additional targets. Structural evidence shows that ketamine and its analog phencyclidine (PCP) can directly bind to and activate human opioid receptors. The study identifies key molecular motifs involved in this binding and efficacy modulation, and also reveals the structure of the ligand-free state of the κ opioid receptor. Ketamine exhibits more dynamic binding than PCP at the orthosteric site, which may explain its distinct pharmacology. These findings indicate that opioid receptors are important for understanding ketamine's clinical versatility.