Structural basis of ligand recognition at the human MT 1 melatonin receptor

Benjamin Stauch, Linda C. Johansson, John D. McCorvy, Nilkanth Patel, Gye Won Han, Xi Ping Huang, Cornelius Gati, Alexander Batyuk, Samuel T. Slocum, Andrii Ishchenko, Wolfgang Brehm, Thomas A. White, Nairie Michaelian, Caleb Madsen, Lan Zhu, Thomas D. Grant, Jessica M. Grandner, Anna Shiriaeva, Reid H.J. Olsen, Alexandra R. Tribo & 7 others Saïd Yous, Raymond C. Stevens, Uwe Weierstall, Vsevolod Katritch, Bryan L. Roth, Wei Liu, Vadim Cherezov

Research output: Contribution to journalLetter

4 Citations (Scopus)

Abstract

Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that maintains circadian rhythms 1 by synchronization to environmental cues and is involved in diverse physiological processes 2 such as the regulation of blood pressure and core body temperature, oncogenesis, and immune function 3 . Melatonin is formed in the pineal gland in a light-regulated manner 4 by enzymatic conversion from 5-hydroxytryptamine (5-HT or serotonin), and modulates sleep and wakefulness 5 by activating two high-affinity G-protein-coupled receptors, type 1A (MT 1 ) and type 1B (MT 2 ) 3,6 . Shift work, travel, and ubiquitous artificial lighting can disrupt natural circadian rhythms; as a result, sleep disorders affect a substantial population in modern society and pose a considerable economic burden 7 . Over-the-counter melatonin is widely used to alleviate jet lag and as a safer alternative to benzodiazepines and other sleeping aids 8,9 , and is one of the most popular supplements in the United States 10 . Here, we present high-resolution room-temperature X-ray free electron laser (XFEL) structures of MT 1 in complex with four agonists: the insomnia drug ramelteon 11 , two melatonin analogues, and the mixed melatonin–serotonin antidepressant agomelatine 12,13 . The structure of MT 2 is described in an accompanying paper 14 . Although the MT 1 and 5-HT receptors have similar endogenous ligands, and agomelatine acts on both receptors, the receptors differ markedly in the structure and composition of their ligand pockets; in MT 1 , access to the ligand pocket is tightly sealed from solvent by extracellular loop 2, leaving only a narrow channel between transmembrane helices IV and V that connects it to the lipid bilayer. The binding site is extremely compact, and ligands interact with MT 1 mainly by strong aromatic stacking with Phe179 and auxiliary hydrogen bonds with Asn162 and Gln181. Our structures provide an unexpected example of atypical ligand entry for a non-lipid receptor, lay the molecular foundation of ligand recognition by melatonin receptors, and will facilitate the design of future tool compounds and therapeutic agents, while their comparison to 5-HT receptors yields insights into the evolution and polypharmacology of G-protein-coupled receptors.

Original languageEnglish (US)
Pages (from-to)284-288
Number of pages5
JournalNature
Volume569
Issue number7755
DOIs
StatePublished - May 9 2019

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Melatonin Receptors
Ligands
S 20098
Melatonin
Serotonin
Serotonin Receptors
G-Protein-Coupled Receptors
Circadian Rhythm
Polypharmacology
5-Methoxytryptamine
Physiological Phenomena
Pineal Gland
Wakefulness
Sleep Initiation and Maintenance Disorders
Lipid Bilayers
Body Temperature
Lighting
Benzodiazepines
Antidepressive Agents
Cues

ASJC Scopus subject areas

  • General

Cite this

Stauch, B., Johansson, L. C., McCorvy, J. D., Patel, N., Han, G. W., Huang, X. P., ... Cherezov, V. (2019). Structural basis of ligand recognition at the human MT 1 melatonin receptor Nature, 569(7755), 284-288. https://doi.org/10.1038/s41586-019-1141-3

Structural basis of ligand recognition at the human MT 1 melatonin receptor . / Stauch, Benjamin; Johansson, Linda C.; McCorvy, John D.; Patel, Nilkanth; Han, Gye Won; Huang, Xi Ping; Gati, Cornelius; Batyuk, Alexander; Slocum, Samuel T.; Ishchenko, Andrii; Brehm, Wolfgang; White, Thomas A.; Michaelian, Nairie; Madsen, Caleb; Zhu, Lan; Grant, Thomas D.; Grandner, Jessica M.; Shiriaeva, Anna; Olsen, Reid H.J.; Tribo, Alexandra R.; Yous, Saïd; Stevens, Raymond C.; Weierstall, Uwe; Katritch, Vsevolod; Roth, Bryan L.; Liu, Wei; Cherezov, Vadim.

In: Nature, Vol. 569, No. 7755, 09.05.2019, p. 284-288.

Research output: Contribution to journalLetter

Stauch, B, Johansson, LC, McCorvy, JD, Patel, N, Han, GW, Huang, XP, Gati, C, Batyuk, A, Slocum, ST, Ishchenko, A, Brehm, W, White, TA, Michaelian, N, Madsen, C, Zhu, L, Grant, TD, Grandner, JM, Shiriaeva, A, Olsen, RHJ, Tribo, AR, Yous, S, Stevens, RC, Weierstall, U, Katritch, V, Roth, BL, Liu, W & Cherezov, V 2019, ' Structural basis of ligand recognition at the human MT 1 melatonin receptor ', Nature, vol. 569, no. 7755, pp. 284-288. https://doi.org/10.1038/s41586-019-1141-3
Stauch B, Johansson LC, McCorvy JD, Patel N, Han GW, Huang XP et al. Structural basis of ligand recognition at the human MT 1 melatonin receptor Nature. 2019 May 9;569(7755):284-288. https://doi.org/10.1038/s41586-019-1141-3
Stauch, Benjamin ; Johansson, Linda C. ; McCorvy, John D. ; Patel, Nilkanth ; Han, Gye Won ; Huang, Xi Ping ; Gati, Cornelius ; Batyuk, Alexander ; Slocum, Samuel T. ; Ishchenko, Andrii ; Brehm, Wolfgang ; White, Thomas A. ; Michaelian, Nairie ; Madsen, Caleb ; Zhu, Lan ; Grant, Thomas D. ; Grandner, Jessica M. ; Shiriaeva, Anna ; Olsen, Reid H.J. ; Tribo, Alexandra R. ; Yous, Saïd ; Stevens, Raymond C. ; Weierstall, Uwe ; Katritch, Vsevolod ; Roth, Bryan L. ; Liu, Wei ; Cherezov, Vadim. / Structural basis of ligand recognition at the human MT 1 melatonin receptor In: Nature. 2019 ; Vol. 569, No. 7755. pp. 284-288.
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abstract = "Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that maintains circadian rhythms 1 by synchronization to environmental cues and is involved in diverse physiological processes 2 such as the regulation of blood pressure and core body temperature, oncogenesis, and immune function 3 . Melatonin is formed in the pineal gland in a light-regulated manner 4 by enzymatic conversion from 5-hydroxytryptamine (5-HT or serotonin), and modulates sleep and wakefulness 5 by activating two high-affinity G-protein-coupled receptors, type 1A (MT 1 ) and type 1B (MT 2 ) 3,6 . Shift work, travel, and ubiquitous artificial lighting can disrupt natural circadian rhythms; as a result, sleep disorders affect a substantial population in modern society and pose a considerable economic burden 7 . Over-the-counter melatonin is widely used to alleviate jet lag and as a safer alternative to benzodiazepines and other sleeping aids 8,9 , and is one of the most popular supplements in the United States 10 . Here, we present high-resolution room-temperature X-ray free electron laser (XFEL) structures of MT 1 in complex with four agonists: the insomnia drug ramelteon 11 , two melatonin analogues, and the mixed melatonin–serotonin antidepressant agomelatine 12,13 . The structure of MT 2 is described in an accompanying paper 14 . Although the MT 1 and 5-HT receptors have similar endogenous ligands, and agomelatine acts on both receptors, the receptors differ markedly in the structure and composition of their ligand pockets; in MT 1 , access to the ligand pocket is tightly sealed from solvent by extracellular loop 2, leaving only a narrow channel between transmembrane helices IV and V that connects it to the lipid bilayer. The binding site is extremely compact, and ligands interact with MT 1 mainly by strong aromatic stacking with Phe179 and auxiliary hydrogen bonds with Asn162 and Gln181. Our structures provide an unexpected example of atypical ligand entry for a non-lipid receptor, lay the molecular foundation of ligand recognition by melatonin receptors, and will facilitate the design of future tool compounds and therapeutic agents, while their comparison to 5-HT receptors yields insights into the evolution and polypharmacology of G-protein-coupled receptors.",
author = "Benjamin Stauch and Johansson, {Linda C.} and McCorvy, {John D.} and Nilkanth Patel and Han, {Gye Won} and Huang, {Xi Ping} and Cornelius Gati and Alexander Batyuk and Slocum, {Samuel T.} and Andrii Ishchenko and Wolfgang Brehm and White, {Thomas A.} and Nairie Michaelian and Caleb Madsen and Lan Zhu and Grant, {Thomas D.} and Grandner, {Jessica M.} and Anna Shiriaeva and Olsen, {Reid H.J.} and Tribo, {Alexandra R.} and Sa{\"i}d Yous and Stevens, {Raymond C.} and Uwe Weierstall and Vsevolod Katritch and Roth, {Bryan L.} and Wei Liu and Vadim Cherezov",
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T1 - Structural basis of ligand recognition at the human MT 1 melatonin receptor

AU - Stauch, Benjamin

AU - Johansson, Linda C.

AU - McCorvy, John D.

AU - Patel, Nilkanth

AU - Han, Gye Won

AU - Huang, Xi Ping

AU - Gati, Cornelius

AU - Batyuk, Alexander

AU - Slocum, Samuel T.

AU - Ishchenko, Andrii

AU - Brehm, Wolfgang

AU - White, Thomas A.

AU - Michaelian, Nairie

AU - Madsen, Caleb

AU - Zhu, Lan

AU - Grant, Thomas D.

AU - Grandner, Jessica M.

AU - Shiriaeva, Anna

AU - Olsen, Reid H.J.

AU - Tribo, Alexandra R.

AU - Yous, Saïd

AU - Stevens, Raymond C.

AU - Weierstall, Uwe

AU - Katritch, Vsevolod

AU - Roth, Bryan L.

AU - Liu, Wei

AU - Cherezov, Vadim

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N2 - Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that maintains circadian rhythms 1 by synchronization to environmental cues and is involved in diverse physiological processes 2 such as the regulation of blood pressure and core body temperature, oncogenesis, and immune function 3 . Melatonin is formed in the pineal gland in a light-regulated manner 4 by enzymatic conversion from 5-hydroxytryptamine (5-HT or serotonin), and modulates sleep and wakefulness 5 by activating two high-affinity G-protein-coupled receptors, type 1A (MT 1 ) and type 1B (MT 2 ) 3,6 . Shift work, travel, and ubiquitous artificial lighting can disrupt natural circadian rhythms; as a result, sleep disorders affect a substantial population in modern society and pose a considerable economic burden 7 . Over-the-counter melatonin is widely used to alleviate jet lag and as a safer alternative to benzodiazepines and other sleeping aids 8,9 , and is one of the most popular supplements in the United States 10 . Here, we present high-resolution room-temperature X-ray free electron laser (XFEL) structures of MT 1 in complex with four agonists: the insomnia drug ramelteon 11 , two melatonin analogues, and the mixed melatonin–serotonin antidepressant agomelatine 12,13 . The structure of MT 2 is described in an accompanying paper 14 . Although the MT 1 and 5-HT receptors have similar endogenous ligands, and agomelatine acts on both receptors, the receptors differ markedly in the structure and composition of their ligand pockets; in MT 1 , access to the ligand pocket is tightly sealed from solvent by extracellular loop 2, leaving only a narrow channel between transmembrane helices IV and V that connects it to the lipid bilayer. The binding site is extremely compact, and ligands interact with MT 1 mainly by strong aromatic stacking with Phe179 and auxiliary hydrogen bonds with Asn162 and Gln181. Our structures provide an unexpected example of atypical ligand entry for a non-lipid receptor, lay the molecular foundation of ligand recognition by melatonin receptors, and will facilitate the design of future tool compounds and therapeutic agents, while their comparison to 5-HT receptors yields insights into the evolution and polypharmacology of G-protein-coupled receptors.

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