XFEL structures of the human MT2 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 A.; Weierstall, Uwe; Yous, Saïd; Stevens, Raymond C.; Liu, Wei; Roth, Bryan L.; Katritch, Vsevolod; Cherezov, Vadim

doi:10.1038/s41586-019-1144-0

Title: XFEL structures of the human MT2 melatonin receptor reveal the basis of subtype selectivity

Journal Article · Wed Apr 24 00:00:00 EDT 2019 · Nature (London)

DOI:https://doi.org/10.1038/s41586-019-1144-0· OSTI ID:1528825

Johansson, Linda C. ^[1]; Stauch, Benjamin ^[1]; McCorvy, John D. ^[2]; Han, Gye Won ^[1]; Patel, Nilkanth ^[1]; Huang, Xi-Ping ^[2]; Batyuk, Alexander ^[3]; Gati, Cornelius ^[4]; Slocum, Samuel T. ^[2]; Li, Chufeng ^[5]; Grandner, Jessica M. ^[1]; Hao, Shuming ^[1]; Olsen, Reid H. J. ^[2]; Tribo, Alexandra R. ^[2]; Zaare, Sahba ^[5]; Zhu, Lan ^[5]; Zatsepin, Nadia A. ^[5]; Weierstall, Uwe ^[5]; Yous, Saïd ^[6]; Stevens, Raymond C. ^[1] more »

Univ. of Southern California, Los Angeles, CA (United States)
Univ. of North Carolina, Chapel Hill, NC (United States)
SLAC National Accelerator Lab., Menlo Park, CA (United States). Linac Coherent Light Source (LCLS)
SLAC National Accelerator Lab., Menlo Park, CA (United States); Stanford Univ., CA (United States)
Arizona State Univ., Tempe, AZ (United States)
Univ. de Lille, Lille (United States)

The human MT₁ and MT₂ melatonin receptors are G-protein-coupled receptors (GPCRs) that help to regulate circadian rhythm and sleep patterns. Drug development efforts have targeted both receptors for the treatment of insomnia, circadian rhythm and mood disorders, and cancer, and MT₂ has also been implicated in type 2 diabetes. Here in this paper we report X-ray free electron laser (XFEL) structures of the human MT₂ receptor in complex with the agonists 2-phenylmelatonin (2-PMT) and ramelteon6 at resolutions of 2.8 Å and 3.3 Å, respectively, along with two structures of function-related mutants: H208^5.46A (superscripts represent the Ballesteros–Weinstein residue numbering nomenclature7) and N86^2.50D, obtained in complex with 2-PMT. Comparison of the structures of MT₂ with a published structure of MT₁ reveals that, despite conservation of the orthosteric ligand-binding site residues, there are notable conformational variations as well as differences in [³H]melatonin dissociation kinetics that provide insights into the selectivity between melatonin receptor subtypes. A membrane-buried lateral ligand entry channel is observed in both MT₁ and MT₂, but in addition the MT₂ 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 MT₂. 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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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH); National Science Foundation (NSF); Swedish Research Council (SRC)

Grant/Contract Number:: AC02-76SF00515; R35 GM127086; R21 DA042298; R01 GM124152; U24DK116195; R01MH112205; 1565180

OSTI ID:: 1528825

Journal Information:: Nature (London), Vol. 569, Issue 7755; ISSN 0028-0836

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 77 works

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