Structural basis of ligand recognition at the human MT1 melatonin receptor

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

doi:10.1038/s41586-019-1141-3

Cited by 166 publications

(243 citation statements)

References 77 publications

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“…Here, we demonstrated that MT promoted HSC and MK proliferation as well as PPF and platelet release through MT1 receptor. This is consistent with the observation that its precursor, 5‐HT, has a similar effect on platelet production, because MT1 receptor shares homogenous endogenous ligands . Although we also observed MT2 expression in MKs, the inhibition of MT2 receptor exerted no obvious effect.…”

Section: Discussionsupporting

confidence: 92%

“…This is consistent with the observation that its precursor, 5-HT, has a similar effect on platelet production, because MT1 receptor shares homogenous endogenous ligands. 26,27 Although we also observed MT2 expression in MKs, the inhibition of MT2 receptor exerted no obvious effect. 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.…”

Section: Discussionmentioning

confidence: 56%

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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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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 56%

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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“…In 1996, Landau [58] first crystallized the bacterial rhodopsin protein by the LCP technique. Subsequently, a variety of membrane protein structures, including G protein-coupled receptors (GPCRs), was obtained by LCP technology [59][60][61][62][63][64][65]. GPCRs mediate signaling pathways and participate in the regulation of a variety of physiological processes and are important drug targets.…”

Section: High-viscosity Extrusion (Hve) Injectormentioning

confidence: 99%

A guide to sample delivery systems for serial crystallography

et al. 2019

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Crystallography has made a notable contribution to our knowledge of structural biology. For traditional crystallography experiments, the growth of crystals with large size and high quality is crucial, and it remains one of the bottlenecks. In recent years, the successful application of serial femtosecond crystallography (SFX) provides a new choice when only numerous microcrystals can be obtained. The intense pulsed radiation of X‐ray free‐electron lasers (XFELs) enables the data collection of small‐sized crystals, making the size of crystals no longer a limiting factor. The ultrafast pulses of XFELs can achieve ‘diffraction before destruction’, which effectively avoids radiation damage and realizes diffraction near physiological temperatures. More recently, the SFX has been expanded to serial crystallography (SX) that can additionally employ synchrotron radiation as the light source. In addition to the traditional ones, these techniques provide complementary opportunities for structural determination. The development of SX experiments strongly relies on the advancement of hardware including the sample delivery system, the X‐ray source, and the X‐ray detector. Here, in this review, we categorize the existing sample delivery systems, summarize their progress, and propose their future prospectives.

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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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Structural basis of ligand recognition at the human MT1 melatonin receptor

Cited by 166 publications

References 77 publications

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

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

A guide to sample delivery systems for serial crystallography

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

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