XFEL structures of the human MT 2 melatonin receptor reveal the basis of subtype selectivity

Linda C. Johansson, Benjamin Stauch, John D. McCorvy, Gye Won Han, Nilkanth Patel, Xi Ping Huang, Alexander Batyuk, Cornelius Gati, Samuel T. Slocum, Chufeng Li, Jessica M. Grandner, Shuming Hao, Reid H.J. Olsen, Alexandra R. Tribo, Sahba Zaare, Lan Zhu, Nadia Zatsepin, Uwe Weierstall, Saïd Yous, Raymond C. Stevens & 4 others Wei Liu, Bryan L. Roth, Vsevolod Katritch, Vadim Cherezov

Research output: Contribution to journalLetter

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Abstract

The human MT 1 and MT 2 melatonin receptors 1,2 are G-protein-coupled receptors (GPCRs) that help to regulate circadian rhythm and sleep patterns 3 . Drug development efforts have targeted both receptors for the treatment of insomnia, circadian rhythm and mood disorders, and cancer 3 , and MT 2 has also been implicated in type 2 diabetes 4,5 . Here we report X-ray free electron laser (XFEL) structures of the human MT 2 receptor in complex with the agonists 2-phenylmelatonin (2-PMT) and ramelteon 6 at resolutions of 2.8 Å and 3.3 Å, respectively, along with two structures of function-related mutants: H208 5.46 A (superscripts represent the Ballesteros–Weinstein residue numbering nomenclature 7 ) and N86 2.50 D, obtained in complex with 2-PMT. Comparison of the structures of MT 2 with a published structure 8 of MT 1 reveals that, despite conservation of the orthosteric ligand-binding site residues, there are notable conformational variations as well as differences in [ 3 H]melatonin dissociation kinetics that provide insights into the selectivity between melatonin receptor subtypes. A membrane-buried lateral ligand entry channel is observed in both MT 1 and MT 2 , but in addition the MT 2 structures reveal a narrow opening towards the solvent in the extracellular part of the receptor. We provide functional and kinetic data that support a prominent role for intramembrane ligand entry in both receptors, and suggest that there might also be an extracellular entry path in MT 2 . Our findings contribute to a molecular understanding of melatonin receptor subtype selectivity and ligand access modes, which are essential for the design of highly selective melatonin tool compounds and therapeutic agents.

Original languageEnglish (US)
Pages (from-to)289-292
Number of pages4
JournalNature
Volume569
Issue number7755
DOIs
StatePublished - May 9 2019

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Melatonin Receptors
Lasers
X-Rays
Electrons
Ligands
Melatonin
CCR10 Receptors
Chronobiology Disorders
Sleep Initiation and Maintenance Disorders
Circadian Rhythm
Mood Disorders
Terminology
Type 2 Diabetes Mellitus
Sleep
Binding Sites
Membranes
Therapeutics
Pharmaceutical Preparations
Neoplasms
2-phenylmelatonin

ASJC Scopus subject areas

  • General

Cite this

Johansson, L. C., Stauch, B., McCorvy, J. D., Han, G. W., Patel, N., Huang, X. P., ... Cherezov, V. (2019). XFEL structures of the human MT 2 melatonin receptor reveal the basis of subtype selectivity Nature, 569(7755), 289-292. https://doi.org/10.1038/s41586-019-1144-0

XFEL structures of the human MT 2 melatonin receptor reveal the basis of subtype selectivity . / Johansson, Linda C.; Stauch, Benjamin; McCorvy, John D.; Han, Gye Won; Patel, Nilkanth; Huang, Xi Ping; Batyuk, Alexander; Gati, Cornelius; Slocum, Samuel T.; Li, Chufeng; Grandner, Jessica M.; Hao, Shuming; Olsen, Reid H.J.; Tribo, Alexandra R.; Zaare, Sahba; Zhu, Lan; Zatsepin, Nadia; Weierstall, Uwe; Yous, Saïd; Stevens, Raymond C.; Liu, Wei; Roth, Bryan L.; Katritch, Vsevolod; Cherezov, Vadim.

In: Nature, Vol. 569, No. 7755, 09.05.2019, p. 289-292.

Research output: Contribution to journalLetter

Johansson, LC, Stauch, B, McCorvy, JD, Han, GW, Patel, N, Huang, XP, Batyuk, A, Gati, C, Slocum, ST, Li, C, Grandner, JM, Hao, S, Olsen, RHJ, Tribo, AR, Zaare, S, Zhu, L, Zatsepin, N, Weierstall, U, Yous, S, Stevens, RC, Liu, W, Roth, BL, Katritch, V & Cherezov, V 2019, ' XFEL structures of the human MT 2 melatonin receptor reveal the basis of subtype selectivity ', Nature, vol. 569, no. 7755, pp. 289-292. https://doi.org/10.1038/s41586-019-1144-0
Johansson LC, Stauch B, McCorvy JD, Han GW, Patel N, Huang XP et al. XFEL structures of the human MT 2 melatonin receptor reveal the basis of subtype selectivity Nature. 2019 May 9;569(7755):289-292. https://doi.org/10.1038/s41586-019-1144-0
Johansson, Linda C. ; Stauch, Benjamin ; McCorvy, John D. ; Han, Gye Won ; Patel, Nilkanth ; Huang, Xi Ping ; Batyuk, Alexander ; Gati, Cornelius ; Slocum, Samuel T. ; Li, Chufeng ; Grandner, Jessica M. ; Hao, Shuming ; Olsen, Reid H.J. ; Tribo, Alexandra R. ; Zaare, Sahba ; Zhu, Lan ; Zatsepin, Nadia ; Weierstall, Uwe ; Yous, Saïd ; Stevens, Raymond C. ; Liu, Wei ; Roth, Bryan L. ; Katritch, Vsevolod ; Cherezov, Vadim. / XFEL structures of the human MT 2 melatonin receptor reveal the basis of subtype selectivity In: Nature. 2019 ; Vol. 569, No. 7755. pp. 289-292.
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abstract = "The human MT 1 and MT 2 melatonin receptors 1,2 are G-protein-coupled receptors (GPCRs) that help to regulate circadian rhythm and sleep patterns 3 . Drug development efforts have targeted both receptors for the treatment of insomnia, circadian rhythm and mood disorders, and cancer 3 , and MT 2 has also been implicated in type 2 diabetes 4,5 . Here we report X-ray free electron laser (XFEL) structures of the human MT 2 receptor in complex with the agonists 2-phenylmelatonin (2-PMT) and ramelteon 6 at resolutions of 2.8 {\AA} and 3.3 {\AA}, respectively, along with two structures of function-related mutants: H208 5.46 A (superscripts represent the Ballesteros–Weinstein residue numbering nomenclature 7 ) and N86 2.50 D, obtained in complex with 2-PMT. Comparison of the structures of MT 2 with a published structure 8 of MT 1 reveals that, despite conservation of the orthosteric ligand-binding site residues, there are notable conformational variations as well as differences in [ 3 H]melatonin dissociation kinetics that provide insights into the selectivity between melatonin receptor subtypes. A membrane-buried lateral ligand entry channel is observed in both MT 1 and MT 2 , but in addition the MT 2 structures reveal a narrow opening towards the solvent in the extracellular part of the receptor. We provide functional and kinetic data that support a prominent role for intramembrane ligand entry in both receptors, and suggest that there might also be an extracellular entry path in MT 2 . Our findings contribute to a molecular understanding of melatonin receptor subtype selectivity and ligand access modes, which are essential for the design of highly selective melatonin tool compounds and therapeutic agents.",
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T1 - XFEL structures of the human MT 2 melatonin receptor reveal the basis of subtype selectivity

AU - Johansson, Linda C.

AU - Stauch, Benjamin

AU - McCorvy, John D.

AU - Han, Gye Won

AU - Patel, Nilkanth

AU - Huang, Xi Ping

AU - Batyuk, Alexander

AU - Gati, Cornelius

AU - Slocum, Samuel T.

AU - Li, Chufeng

AU - Grandner, Jessica M.

AU - Hao, Shuming

AU - Olsen, Reid H.J.

AU - Tribo, Alexandra R.

AU - Zaare, Sahba

AU - Zhu, Lan

AU - Zatsepin, Nadia

AU - Weierstall, Uwe

AU - Yous, Saïd

AU - Stevens, Raymond C.

AU - Liu, Wei

AU - Roth, Bryan L.

AU - Katritch, Vsevolod

AU - Cherezov, Vadim

PY - 2019/5/9

Y1 - 2019/5/9

N2 - The human MT 1 and MT 2 melatonin receptors 1,2 are G-protein-coupled receptors (GPCRs) that help to regulate circadian rhythm and sleep patterns 3 . Drug development efforts have targeted both receptors for the treatment of insomnia, circadian rhythm and mood disorders, and cancer 3 , and MT 2 has also been implicated in type 2 diabetes 4,5 . Here we report X-ray free electron laser (XFEL) structures of the human MT 2 receptor in complex with the agonists 2-phenylmelatonin (2-PMT) and ramelteon 6 at resolutions of 2.8 Å and 3.3 Å, respectively, along with two structures of function-related mutants: H208 5.46 A (superscripts represent the Ballesteros–Weinstein residue numbering nomenclature 7 ) and N86 2.50 D, obtained in complex with 2-PMT. Comparison of the structures of MT 2 with a published structure 8 of MT 1 reveals that, despite conservation of the orthosteric ligand-binding site residues, there are notable conformational variations as well as differences in [ 3 H]melatonin dissociation kinetics that provide insights into the selectivity between melatonin receptor subtypes. A membrane-buried lateral ligand entry channel is observed in both MT 1 and MT 2 , but in addition the MT 2 structures reveal a narrow opening towards the solvent in the extracellular part of the receptor. We provide functional and kinetic data that support a prominent role for intramembrane ligand entry in both receptors, and suggest that there might also be an extracellular entry path in MT 2 . Our findings contribute to a molecular understanding of melatonin receptor subtype selectivity and ligand access modes, which are essential for the design of highly selective melatonin tool compounds and therapeutic agents.

AB - The human MT 1 and MT 2 melatonin receptors 1,2 are G-protein-coupled receptors (GPCRs) that help to regulate circadian rhythm and sleep patterns 3 . Drug development efforts have targeted both receptors for the treatment of insomnia, circadian rhythm and mood disorders, and cancer 3 , and MT 2 has also been implicated in type 2 diabetes 4,5 . Here we report X-ray free electron laser (XFEL) structures of the human MT 2 receptor in complex with the agonists 2-phenylmelatonin (2-PMT) and ramelteon 6 at resolutions of 2.8 Å and 3.3 Å, respectively, along with two structures of function-related mutants: H208 5.46 A (superscripts represent the Ballesteros–Weinstein residue numbering nomenclature 7 ) and N86 2.50 D, obtained in complex with 2-PMT. Comparison of the structures of MT 2 with a published structure 8 of MT 1 reveals that, despite conservation of the orthosteric ligand-binding site residues, there are notable conformational variations as well as differences in [ 3 H]melatonin dissociation kinetics that provide insights into the selectivity between melatonin receptor subtypes. A membrane-buried lateral ligand entry channel is observed in both MT 1 and MT 2 , but in addition the MT 2 structures reveal a narrow opening towards the solvent in the extracellular part of the receptor. We provide functional and kinetic data that support a prominent role for intramembrane ligand entry in both receptors, and suggest that there might also be an extracellular entry path in MT 2 . Our findings contribute to a molecular understanding of melatonin receptor subtype selectivity and ligand access modes, which are essential for the design of highly selective melatonin tool compounds and therapeutic agents.

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