Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor

Kim, Kuglae; Che, Tao; Panova, Ouliana; DiBerto, Jeffrey F.; Lyu, Jiankun; Krumm, Brian E.; Wacker, Daniel; Robertson, Michael J.; Seven, Alpay B.; Nichols, David E.; Shoichet, Brian K.; Skiniotis, Georgios; Roth, Bryan L.

doi:10.1016/j.cell.2020.08.024

Cited by 347 publications

(500 citation statements)

References 82 publications

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“…14e ). In the PIF motif, the most significant change is the side chain displacement of F424 6.44 upon receptor activation, similar to the observation in the receptor activation of the HTR2A/mini-Gq complex 17 .…”

Section: Resultssupporting

confidence: 74%

“…The muscarinic acetylcholine receptor 1 (M1R)/G 11 complex structure first revealed some distinct features for the G q/11 -coupled receptors, including an extended TM5 and a receptor c-tail/G-protein interaction 16 . Most recently, a 5-HT 2A serotonin receptor (HTR2A)/mini-G q protein complex structure was solved 17 . It is imaginable that with more G q -coupled receptor complex structures being solved, a pattern of receptor/G q engagement can be found.…”

Section: Introductionmentioning

confidence: 99%

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Cryo-EM structure of the human histamine H1 receptor/Gq complex

Xia

Wang

et al. 2021

Nat Commun

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Histamine receptors play important roles in various pathophysiological conditions and are effective targets for anti-allergy treatment, however the mechanism of receptor activation remain elusive. Here, we present the cryo-electron microscopy (cryo-EM) structure of the human H1R in complex with a Gq protein in an active conformation via a NanoBiT tethering strategy. The structure reveals that histamine activates receptor via interacting with the key residues of both transmembrane domain 3 (TM3) and TM6 to squash the binding pocket on the extracellular side and to open the cavity on the intracellular side for Gq engagement in a model of “squash to activate and expand to deactivate”. The structure also reveals features for Gq coupling, including the interaction between intracellular loop 2 (ICL2) and the αN-β junction of Gq/11 protein. The detailed analysis of our structure will provide a framework for understanding G-protein coupling selectivity and clues for designing novel antihistamines.

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Section: Resultssupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Cryo-EM structure of the human histamine H1 receptor/Gq complex

Xia

Wang

et al. 2021

Nat Commun

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“…We compare their influence on extracellular loop dynamics with the unbiased endogenous ligand serotonin (5-HT) by means of molecular dynamics (MD) simulations and dynamic pharmacophores. The analysis of additional biased 5-HT 2B R ligands from the BiasDB , a publicly available database for biased GPCR ligands [ 25 ], and recent structural data of the 5-HT 1A R, 5-HT 1B R, and dopamine D 2 receptor support our findings [ 23 , 26 , 27 , 28 ]. Given the existence of pathway-specific binding site conformations, we discuss implications for structure-based approaches in drug design, providing a route to virtually screen for ligands with a specific signaling profile by using the corresponding receptor conformation as starting point.…”

Section: Introductionsupporting

confidence: 83%

Biased Ligands Differentially Shape the Conformation of the Extracellular Loop Region in 5-HT2B Receptors

Denzinger

Nguyen

Noonan

et al. 2020

IJMS

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G protein-coupled receptors are linked to various intracellular transducers, each pathway associated with different physiological effects. Biased ligands, capable of activating one pathway over another, are gaining attention for their therapeutic potential, as they could selectively activate beneficial pathways whilst avoiding those responsible for adverse effects. We performed molecular dynamics simulations with known β-arrestin-biased ligands like lysergic acid diethylamide and ergotamine in complex with the 5-HT2B receptor and discovered that the extent of ligand bias is directly connected with the degree of closure of the extracellular loop region. Given a loose allosteric coupling of extracellular and intracellular receptor regions, we delineate a concept for biased signaling at serotonin receptors, by which conformational interference with binding pocket closure restricts the signaling repertoire of the receptor. Molecular docking studies of biased ligands gathered from the BiasDB demonstrate that larger ligands only show plausible docking poses in the ergotamine-bound structure, highlighting the conformational constraints associated with bias. This emphasizes the importance of selecting the appropriate receptor conformation on which to base virtual screening workflows in structure-based drug design of biased ligands. As this mechanism of ligand bias has also been observed for muscarinic receptors, our studies provide a general mechanism of signaling bias transferable between aminergic receptors.

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“…The 5-HT2AR is a member of the rhodopsin family of GPCRs that is coupled to G q protein and β-arrestin (βArr) mediated signaling [22-25]. Recent experiments have found the 5-HT2AR preferentially activates G q family members, with moderate activity at G z , and minimal detectible activity at other G i , G 12/13 , and G s -family members [26]. However, the 5-HT2AR binds to both βArr1 and βArr2 proteins in vitro and is complexed with bArr1 and bArr2 in cortical neurons in vivo [25].…”

Section: Introductionmentioning

confidence: 99%

LSD’s effects are differentially modulated in arrestin knockout mice

Nadkarni

et al. 2021

Preprint

Self Cite

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Recent evidence suggests that psychedelic drugs can exert beneficial effects on anxiety, depression, and ethanol and nicotine abuse in humans. However, the hallucinogenic side effects of psychedelics often preclude their clinical use. Lysergic acid diethylamide (LSD) is a prototypical hallucinogen and its psychedelic actions are exerted through the 5HT2A serotonin receptor (5HT2AR). 5HT2AR activation stimulates Gq and arrestin (Arr) mediated signaling. To separate effects of these signaling modes, we have used Arr1 and Arr2 mice. We find that LSD stimulates motor activities to similar extents in WT and Arr1 KO mice, with non-significant effects in Arr2 KOs. LSD robustly stimulates many surrogates of psychedelic drug actions including head twitches, grooming, retrograde walking, and nose poking in WT and Arr1 KO animals. In contrast, LSD only slightly stimulates head twitches in Arr2 KO mice, without effects on retrograde walking or nose poking. The 5HT2AR antagonist MDL100907 (MDL) blocks these LSD effects. LSD also disrupts prepulse inhibition (PPI) in WT and Arr1 KOs. PPI is unaffected in Arr2 KOs. MDL restores PPI in WT mice, but this antagonist is without effect and haloperidol is required in Arr1 KOs. LSD produces a biphasic body-temperature response in WT mice, a monophasic response in Arr1 KOs, and is without effect in Arr2 mutants. Both MDL and the 5HT1AR antagonist, WAY100635 (WAY), block the effects of LSD on body temperatures in WT mice, whereas WAY is effective in Arr1 KOs. Collectively, these results reveal that LSD produces diverse behavioral effects through Arr1 and Arr2, and that the psychedelic drug-like actions of LSD appear to require Arr2.

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Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor

Cited by 347 publications

References 82 publications

Cryo-EM structure of the human histamine H1 receptor/Gq complex

Cryo-EM structure of the human histamine H1 receptor/Gq complex

Biased Ligands Differentially Shape the Conformation of the Extracellular Loop Region in 5-HT2B Receptors

LSD’s effects are differentially modulated in arrestin knockout mice

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