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, A.; Gati, Cornelius; Slocum, Samuel T.; Li, Chufeng; Grandner, Jessica M.; Hao, Shuming; Olsen, Reid H.J.; Tribo, Alexandra R.; Zaare, Sahba; Zhu, Liya; Zatsepin, Nadia A.; Weierstall, Uwe; Yous, Saı̈d; Stevens, Raymond C.; Liu, Wei; Roth, Bryan L.; Katritch, Vsevolod; Cherezov, Vadim

doi:10.1038/s41586-019-1144-0

Cited by 112 publications

(155 citation statements)

References 47 publications

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“…Consistently, ICOA‐9 shows both, MT 2 selectivity and signaling bias, as well as 4‐phenyl‐2‐propionamidotetralin (4‐P‐PDOT) (Figure C), the gold‐standard ligand to show MT 2 ‐dependent effects, which has also been shown to display signaling bias . Molecular docking of 4‐P‐PDOT and superposition with 2‐PMT in the crystal structure indicates that the phenyl side chains of 4‐P‐PDOT and 2‐PMT occupy a similar but not identical space (see the space limited by the red circle in . The fact that the cis enantiomer of 4‐P‐PDOT has more than 100 times higher affinity for human MT 2 than the trans enantiomer indicates that the phenyl and the propionamido side chains are oriented toward the same side compared to the tetralin ring.…”

Section: Introductionmentioning

confidence: 70%

Melatonin receptor structures shed new light on melatonin research

Cecon

Liu

Jockers

2019

Journal of Pineal Research

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The tryptophan derivative melatonin is an evolutionary old molecule that is involved in a pleiotropy of physiological functions. In humans, age-related decline of circulating melatonin levels and/or dysregulation of its circadian synthesis pattern have been associated with several disorders and disease states. Several molecular targets have been proposed for melatonin since its discovery, in 1959. Among them, melatonin MT 1 and MT 2 receptors are the best characterized melatonin targets, mediating melatonin effects in a variety of tissues. They belong to the superfamily of G protein-coupled receptors. Two back-to-back articles published in the "Nature" Journal earlier this year present the first crystal structures of the human MT 1 and MT 2 in its inactive states. Here, we will briefly outline the discovery path of melatonin receptors until their structural elucidation and discuss how these new findings will guide future research toward a better understanding of their function and rational drug design. K E Y W O R D Scrystal structure, dimers, GPCR, melatonin

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Section: Introductionmentioning

confidence: 70%

Melatonin receptor structures shed new light on melatonin research

Cecon

Liu

Jockers

2019

Journal of Pineal Research

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“…The difference between MT1 and MT2 receptor may be attributed in part to the sharp decrease in MT2 receptor expression observed in the later stages of thrombopoiesis ( Figure S11) or restricted binding site of MT2 receptor, preventing MT access. 28 Another binding site, MT3 receptor, with low-affinity for MT, is involved in the protection of cells from oxidative injuries by inhibition of electron transfer. 29,30 Therefore, the effect of MT3 receptor on MK activities needs to be further evaluated.…”

Section: Discussionmentioning

confidence: 99%

Melatonin enhances thrombopoiesis through ERK1/2 and Akt activation orchestrated by dual adaptor for phosphotyrosine and 3‐phosphoinositides

Chen

Wang

et al. 2020

Journal of Pineal Research

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Melatonin (MT), endogenously secreted by the pineal gland, is closely related to multiple biological processes; however, its effect on thrombopoiesis is still not well illustrated. Here, we demonstrate that MT administration can elevate peripheral platelet levels. Analysis of different stages in thrombopoiesis reveals that MT has the capacity to promote the expansion of CD34+ and CD41+ cells, and accelerate proplatelet formation (PPF) and platelet production. Furthermore, in vivo experiments show that MT has a potential therapeutic effect on radiation‐induced thrombocytopenia. The underlying mechanism suggests that both extracellular signal‐regulated kinase 1/2 (ERK1/2) and Akt signaling are involved in the processes of thrombopoiesis facilitated by MT. Interestingly, in addition to the direct regulation of Akt signaling by its upstream phosphoinositide 3‐kinase (PI3K), ERK1/2 signaling is also regulated by PI3K via its effector, dual adaptor for phosphotyrosine and 3‐phosphoinositides (DAPP1), in megakaryocytes after MT treatment. Moreover, the expression level of DAPP1 during megakaryocyte differentiation is closely related to the activation of ERK1/2 and Akt at different stages of thrombopoiesis. In conclusion, our data suggest that MT treatment can promote thrombopoiesis, which is modulated by the DAPP1‐orchestrated activation of ERK1/2 and Akt signaling.

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“…Different receptors have different sized loops and N‐ and C‐termini. The general structure of GPCRs was described by crystallographers and structuralists; all GPCRs have a quite uniform structure, including melatonin receptors . Indeed, the field of melatonin receptors has made remarkably important structural advances, as recently reviewed by Cecon et al…”

Section: Receptors and Drugs: The Pastmentioning

confidence: 99%

“…Those basic structures were decorated with a paramount of functions (see Zlotos et al and Spadoni et al for chemical details). Moreover, the crystal structures of MT 1 and MT 2 receptors were recently published . These structures provide the opportunity to find more diverse antagonistic compounds.…”

Section: The 5d Space Exemplified By Melatonin Receptorsmentioning

confidence: 99%

The five dimensions of receptor pharmacology exemplified by melatonin receptors: An opinion

Boutin

Legros

2019

Pharmacology Res & Perspec

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Receptology has been complicated with enhancements in our knowledge of G‐protein‐coupled‐receptor (GPCR) biochemistry. This complexity is exemplified by the pharmacology of melatonin receptors. Here, we describe the complexity of GPCR biochemistry in five dimensions: (a) receptor expression, particularly in organs/tissues that are only partially understood; (b) ligands and receptor‐associated proteins (interactome); (c) receptor function, which might be more complex than the known G‐protein‐coupled systems; (d) ligand bias, which favors a particular pathway; and (e) receptor dimerization, which might concern all receptors coexpressed in the same cell. Thus, receptor signaling might be modified or modulated, depending on the nature of the receptor complex. Fundamental studies are needed to clarify these points and find new ways to tackle receptor functionality. This opinion article emphasizes the global questions attached to new descriptions of GPCRs and aims to raise our awareness of the tremendous complexity of modern receptology.

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

Cited by 112 publications

References 47 publications

Melatonin receptor structures shed new light on melatonin research

Melatonin receptor structures shed new light on melatonin research

Melatonin enhances thrombopoiesis through ERK1/2 and Akt activation orchestrated by dual adaptor for phosphotyrosine and 3‐phosphoinositides

The five dimensions of receptor pharmacology exemplified by melatonin receptors: An opinion

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