The Mechanism and Function of Agonist-Induced Trafficking of G-protein Coupled Receptors

G-protein-coupled receptors (GPCRs), which constitute the largest family of cell surface receptors, were originally thought to function as monomers, but are now recognized as being able to act in a wide range of oligomeric states and indeed, it is known that the oligomerization state of a GPCR can modulate its pharmacology and function. A number of experimental techniques have been devised to study GPCR oligomerization including those based upon traditional biochemistry such as blue-native PAGE (BN-PAGE), co-immunoprecipitation (Co-IP) and protein-fragment complementation assays (PCAs), those based upon resonance energy transfer, FRET, time-resolved FRET (TR-FRET), FRET spectrometry and bioluminescence resonance energy transfer (BRET). Those based upon microscopy such as FRAP, total internal reflection fluorescence microscopy (TIRFM), spatial intensity distribution analysis (SpIDA) and various single molecule imaging techniques. Finally with the solution of a growing number of crystal structures, X-ray crystallography must be acknowledged as an important source of discovery in this field. A different, but in many ways complementary approach to the use of more traditional experimental techniques, are those involving computational methods that possess obvious merit in the study of the dynamics of oligomer formation and function. Here, we summarize the latest developments that have been made in the methods used to study GPCR oligomerization and give an overview of their application.

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Unraveling the Structure and Function of G Protein-Coupled Receptors Through NMR Spectroscopy

Current Pharmaceutical Design ◽

10.2174/138161209789824803 ◽

2009 ◽

Vol 15 (35) ◽

pp. 4003-4016 ◽

Cited By ~ 22

Author(s):

Irina Tikhonova ◽

Stefano Costanzi

Keyword(s):

Nmr Spectroscopy ◽

G Protein ◽

Structure And Function ◽

G Protein Coupled Receptors ◽

And Function ◽

G Protein Coupled

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Structural Basis for Allosteric Modulation of Class B G Protein–Coupled Receptors

The Annual Review of Pharmacology and Toxicology ◽

10.1146/annurev-pharmtox-010919-023301 ◽

2020 ◽

Vol 60 (1) ◽

pp. 89-107 ◽

Cited By ~ 7

Author(s):

Denise Wootten ◽

Laurence J. Miller

Keyword(s):

G Protein ◽

Allosteric Modulation ◽

G Protein Coupled Receptors ◽

Structural Basis ◽

Allosteric Modulators ◽

Class B ◽

Endogenous Proteins ◽

And Function ◽

Agonist Ligands ◽

G Protein Coupled

Recent advances in our understanding of the structure and function of class B G protein–coupled receptors (GPCRs) provide multiple opportunities for targeted development of allosteric modulators. Given the pleiotropic signaling patterns emanating from these receptors in response to a variety of natural agonist ligands, modulators have the potential to sculpt the responses to meet distinct needs of different groups of patients. In this review, we provide insights into how this family of GPCRs differs from the rest of the superfamily, how orthosteric agonists bind and activate these receptors, the potential for allosteric modulators to interact with various regions of these targets, and the allosteric influence of endogenous proteins on the pharmacology of these receptors, all of which are important considerations when developing new therapies.

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