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In this video, we discuss the structure of LSD in complex with one of its major targets in the brain, the 5-HT2B receptor, the first such structure for any psychedelic drug. The results of the study we focused on (Wacker et al. 2017) shed light on the molecular mechanisms underlying LSD’s ability to induce hallucinations with greater duration and potency than closely related compounds. As in the endogenous agonist 5-HT, LSD contains a tryptamine moiety but also features a diethylamide substituent known to be important for its psychedelic properties. The tryptamine moiety sits in the endogenous agonist binding site (the orthosteric pocket) and is anchored via a salt bridge between its nitrogen and a conserved aspartate side chain. The ergoline ring system of LSD is further stabilized by hydrophobic interactions with the receptor core. The diethylamide group of LSD binds with its ethyl moieties in a stereospecific manner reminiscent of the legs of a bicyclist. The authors go on to show, by using chemical analogs, that if the ethyl ‘‘legs’’ are constrained in a configuration opposite to that observed in the complex, then there is a dramatic loss of arrestin recruitment, but not of G protein coupling (biased signaling). The data strongly indicate that stereoselective binding of LSD to the receptor is critical for its ability to preferentially recruit arrestin and, ultimately, for its psychedelic properties. An LSD-triggered acid trip lasts 6–15 hr, even though its clearance from the body is much faster. So what underlies the prolonged effect of LSD? Wacker et al provide a potential molecular explanation: an extracellular loop of the HT2B receptor (and likely of HT2A) forms a lid covering the ligand-binding site, thereby slowing the dissociation of LSD from the receptor. Residues in the lid directly interact with LSD, and disrupting this interaction by site-directed mutagenesis results in shorter residency time of LSD. Remarkably, a mutant that reduces interactions between the lid and LSD also attenuates arrestin recruitment while leaving the activation of G protein signaling intact, supporting the idea that specific contacts between the lid and LSD are critical for stabilizing the receptor in a conformational state that promotes the psychedelic effects of the drug. This work is important because it provides a roadmap for the rational design of drugs that are more biased toward desirable outcomes. In the case of LSD, this would entail the synthesis of variants that retain therapeutic benefit without psychedelic effects, but it remains to be seen if these can truly be separated. Thanks to our guest speaker Asher Brandt, molecular pharmacology PhD student at the University of Saskatchewan, Canada, who runs his own YouTube channel dedicated to the chemistry of psychedelics: References: Wacker et al. (2017). Crystal Structure of an LSD-Bound Human Serotonin Receptor. Cell. 168, 377–389. Chen and Tesmer (2017). A Receptor on Acid. Cell. Vol 168, 339-34. DOWNLOAD NANOME FOR FREE Oculus: Steam: Viveport: SideQuest: SUPPORTED VR HEADSETS Oculus Rift Oculus Quest HTC Vive Complete list: CONNECT WITH US Twitter: LinkedIn: Facebook: Instagram: ABOUT NANOME Website: Step into Nanome and experience the world at the molecular level. From drug discovery to chemistry class, Nanome is a powerful tool for research and education. Visualize, design, and simulate chemical compounds, proteins, and nucleic acids like never before. Collaborate remotely in real-time, save workspaces, and share. Leading pharmaceutical and biotech companies use Nanome to accelerate drug discovery and collaborate with distributed teams across the globe. Educators at top universities use Nanome to teach chemistry in virtual reality, allowing students to explore shapes of proteins and drug compounds and to learn how these structures explain function. Be sure to also check out our blockchain platform, Matryx, which will serve as the backend IP tracking mechanism for Nanome. More info at
