Molecular Mechanisms of GPCR Signaling: A Structural Perspective

Gurevich, Vsevolod V.; Gurevich, Eugenia V.

doi:10.3390/ijms18122519

Cited by 67 publications

(44 citation statements)

References 103 publications

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“…In trying to generalize a perspective about the outcome of this work to GPCRs as a family, it is worth nothing that the mechanism of GPCRs as a whole is probably shared between most members of the family, and the details of the interactions with partners and subsequent effects on them and cascading cellular response, is probably common between all members that bind the same cognate G protein (eg, G s ). The common mechanism assumption is probably best supported by GPCR architecture being well preserved (even in cases of low sequence similarity) and the common binding pocket for G protein partners, on the cytoplasmic face of different receptors, and shows that our results could serve as a cornerstone in further understanding of GLP1R, or other GPCRs as well.…”

Section: Resultssupporting

confidence: 54%

A free‐energy landscape for the glucagon‐like peptide 1 receptor GLP1R

Alhadeff

Warshel

2019

Proteins

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G‐protein‐coupled receptors (GPCRs) are among the most important receptors in human physiology and pathology. They serve as master regulators of numerous key processes and are involved in as well as cause debilitating diseases. Consequently, GPCRs are among the most attractive targets for drug design and pharmaceutical interventions (>30% of drugs on the market). The glucagon‐like peptide 1 (GLP‐1) hormone receptor GLP1R is closely involved in insulin secretion by pancreatic β‐cells and constitutes a major druggable target for the development of anti‐diabetes and obesity agents. GLP1R structure was recently solved, with ligands, allosteric modulators and as part of a complex with its cognate G protein. However, the translation of this structural data into structure/function understanding remains limited. The current study functionally characterizes GLP1R with special emphasis on ligand and cellular partner binding interactions and presents a free‐energy landscape as well as a functional model of the activation cycle of GLP1R. Our results should facilitate a deeper understanding of the molecular mechanism underlying GLP1R activation, forming a basis for improved development of targeted therapeutics for diabetes and related disorders.

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Section: Resultssupporting

confidence: 54%

A free‐energy landscape for the glucagon‐like peptide 1 receptor GLP1R

Alhadeff

Warshel

2019

Proteins

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“…It has been reported in nucleated cells that GRKs only transiently interact with GPCRs, and GPCR/GRK interactions are much weaker compared with GPCR/G protein and GPCR/arrestin interactions. 29,30 To assess the interaction between GRK6 and PAR1 during platelet activation, resting or activated platelets lysates were subjected to immunoprecipitation. The results show that there is little or no association of GRK6 with PAR1 in resting platelets.…”

Section: Grk6 Forms a Complex With Par1 During Platelet Activationmentioning

confidence: 99%

GRK6 Regulates the Hemostatic Response to Injury through Its Rate-Limiting Effects on GPCR Signaling in Platelets

Chen

Gupta

Cooper

et al. 2019

Blood

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Inappropriate platelet activation remains a major cause of cardiovascular and cerebrovascular diseases. Most agonists activate platelets through G protein-coupled receptors (GPCRs). However, questions remain about mechanisms that provide negative feedback towards activated GPCRs to limit platelet activation and thrombus formation. Here we provide the first evidence that GPCR kinase 6 (GRK6) serves this role in platelets, using GRK6-/- mice generated by CRISPR-Cas9 genome editing to examine the consequences of GRK6 knockout on GPCR-dependent signaling. Hemostatic thrombi formed in GRK6-/- mice are larger than in WT controls during the early stages of thrombus formation, with a rapid increase of platelet accumulation at site of injury. Platelet activation in the absence of GRK6 is enhanced, but in an agonist-selective manner. Responses to PAR4 agonist peptide or ADP stimulation in GRK6-/- platelets are increased compared to WT control littermates, while the response to TxA2 is normal. Underlying these changes in GRK6-/- platelets is an increase in Ca2+ mobilization, Akt activation, and granule secretion. Furthermore, deletion of GRK6 in human MEG-01 cells causes an increase in Ca2+ response and PAR1 surface expression in response to thrombin. Finally, we show that in human platelets, platelet activation in response to thrombin causes an increase in binding of GRK6 to PAR1, as well as an increase of the phosphorylation of PAR1. Deletion of GRK6 in MEG-01 cells causes a decrease in PAR1 phosphorylation. Collectively, these observations, for the first time, show that 1) GRK6 regulates the hemostatic response to injury by thrombin and ADP, 2) it mediates platelet activation by reducing PAR1/4- and P2Y12-dependent signaling, and 3) GRK6 limits the rate of platelet activation during early stage of thrombus growth and helps prevent inappropriate platelet activation. Disclosures No relevant conflicts of interest to declare.

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“…Humans express only four arrestins, among which the two visual arrestins are specialized to couple to visual receptors, while the two β‐arrestins serve about 800 non‐visual GPCRs . These two β‐arrestins demonstrate a high versatility but low specificity to GPCRs.…”

Section: Gpcr–arrestin Interactionmentioning

confidence: 99%

“…49,50 Humans express only four arrestins, among which the two visual arrestins are specialized to couple to visual receptors, while the two β-arrestins serve about 800 non-visual GPCRs. 51 These two β-arrestins demonstrate a high versatility but low specificity to GPCRs. Arrestin-mediated GPCR signaling starts from arrestin activation and recruitment by the GPCR, which is largely regulated by the phosphorylation code on the receptor's C-terminal tail.…”

Section: Structurementioning

confidence: 99%

Structural biology of G protein‐coupled receptor signaling complexes

Zhou

Melcher

2018

Protein Science

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G protein‐coupled receptors (GPCRs) constitute the largest family of cell surface receptors that mediate numerous cell signaling pathways, and are targets of more than one‐third of clinical drugs. Thanks to the advancement of novel structural biology technologies, high‐resolution structures of GPCRs in complex with their signaling transducers, including G‐protein and arrestin, have been determined. These 3D complex structures have significantly improved our understanding of the molecular mechanism of GPCR signaling and provided a structural basis for signaling‐biased drug discovery targeting GPCRs. Here we summarize structural studies of GPCR signaling complexes with G protein and arrestin using rhodopsin as a model system, and highlight the key features of GPCR conformational states in biased signaling including the sequence motifs of receptor TM6 that determine selective coupling of G proteins, and the phosphorylation codes of GPCRs for arrestin recruitment. We envision the future of GPCR structural biology not only to solve more high‐resolution complex structures but also to show stepwise GPCR signaling complex assembly and disassembly and dynamic process of GPCR signal transduction.

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Molecular Mechanisms of GPCR Signaling: A Structural Perspective

Cited by 67 publications

References 103 publications

A free‐energy landscape for the glucagon‐like peptide 1 receptor GLP1R

A free‐energy landscape for the glucagon‐like peptide 1 receptor GLP1R

GRK6 Regulates the Hemostatic Response to Injury through Its Rate-Limiting Effects on GPCR Signaling in Platelets

Structural biology of G protein‐coupled receptor signaling complexes

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