scholarly journals Crystal structure of β-arrestin 2 in complex with an atypical chemokine receptor phosphopeptide reveals an alternative active conformation

2019 ◽  
Author(s):  
Kyungjin Min ◽  
Hye-Jin Yoon ◽  
Ji Young Park ◽  
Mithu Baidya ◽  
Hemlata Dwivedi ◽  
...  

Abstractβ-arrestins (βarrs) critically regulate signaling and trafficking of G protein-coupled receptors (GPCRs), the largest family of drug targets in the human genome, and there are two isoforms of βarrs: βarr1 and βarr2. Most GPCRs interact with both the heterotrimeric G-proteins and βarrs, inducing distinct downstream signal transduction. However, certain chemokine receptors lack functional G-protein coupling, but they can efficiently recruit βarrs upon agonist-stimulation, and they are referred to as atypical chemokine receptors (ACKRs). Receptor phosphorylation is a key determinant for the binding of βarrs, and understanding the intricate details of receptor-βarr interaction is the next frontier in GPCR structural biology. To date, the high-resolution structures of active βarr1 have been revealed, but the activation mechanism of βarr2 by a phosphorylated GPCR remains elusive. Here, we present a 1.95 Å crystal structure of βarr2 in complex with a phosphopeptide (C7pp) derived from the carboxyl-terminus of ACKR3, also known as CXCR7. The structure of C7pp-bound βarr2 reveals key differences from the previously determined active conformation of βarr1. One of the key differences is that C7pp-bound βarr2 shows a relatively small inter-domain rotation. An antibody-fragment-based conformational sensor and hydrogen/deuterium exchange experiments further corroborate structural features and suggest that the determined structure is an alternative active conformation of βarr2.

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Isabell Kaczmarek ◽  
Tomáš Suchý ◽  
Simone Prömel ◽  
Torsten Schöneberg ◽  
Ines Liebscher ◽  
...  

Abstract G protein-coupled receptors (GPCRs) modulate a variety of physiological functions and have been proven to be outstanding drug targets. However, approximately one-third of all non-olfactory GPCRs are still orphans in respect to their signal transduction and physiological functions. Receptors of the class of Adhesion GPCRs (aGPCRs) are among these orphan receptors. They are characterized by unique features in their structure and tissue-specific expression, which yields them interesting candidates for deorphanization and testing as potential therapeutic targets. Capable of G-protein coupling and non-G protein-mediated function, aGPCRs may extend our repertoire of influencing physiological function. Besides their described significance in the immune and central nervous systems, growing evidence indicates a high importance of these receptors in metabolic tissue. RNAseq analyses revealed high expression of several aGPCRs in pancreatic islets, adipose tissue, liver, and intestine but also in neurons governing food intake. In this review, we focus on aGPCRs and their function in regulating metabolic pathways. Based on current knowledge, this receptor class represents high potential for future pharmacological approaches addressing obesity and other metabolic diseases.


2021 ◽  
Vol 7 (22) ◽  
pp. eabg3362
Author(s):  
Hamidreza Shaye ◽  
Benjamin Stauch ◽  
Cornelius Gati ◽  
Vadim Cherezov

Metabotropic γ-aminobutyric acid G protein–coupled receptors (GABAB) represent one of the two main types of inhibitory neurotransmitter receptors in the brain. These receptors act both pre- and postsynaptically by modulating the transmission of neuronal signals and are involved in a range of neurological diseases, from alcohol addiction to epilepsy. A series of recent cryo-EM studies revealed critical details of the activation mechanism of GABAB. Structures are now available for the receptor bound to ligands with different modes of action, including antagonists, agonists, and positive allosteric modulators, and captured in different conformational states from the inactive apo to the fully active state bound to a G protein. These discoveries provide comprehensive insights into the activation of the GABAB receptor, which not only broaden our understanding of its structure, pharmacology, and physiological effects but also will ultimately facilitate the discovery of new therapeutic drugs and neuromodulators.


Nature ◽  
2007 ◽  
Vol 450 (7168) ◽  
pp. 383-387 ◽  
Author(s):  
Søren G. F. Rasmussen ◽  
Hee-Jung Choi ◽  
Daniel M. Rosenbaum ◽  
Tong Sun Kobilka ◽  
Foon Sun Thian ◽  
...  

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Ramón Cierco Jimenez ◽  
Nil Casajuana-Martin ◽  
Adrián García-Recio ◽  
Lidia Alcántara ◽  
Leonardo Pardo ◽  
...  

Abstract Background Olfactory receptors (ORs) constitute a large family of sensory proteins that enable us to recognize a wide range of chemical volatiles in the environment. By contrast to the extensive information about human olfactory thresholds for thousands of odorants, studies of the genetic influence on olfaction are limited to a few examples. To annotate on a broad scale the impact of mutations at the structural level, here we analyzed a compendium of 119,069 natural variants in human ORs collected from the public domain. Results OR mutations were categorized depending on their genomic and protein contexts, as well as their frequency of occurrence in several human populations. Functional interpretation of the natural changes was estimated from the increasing knowledge of the structure and function of the G protein-coupled receptor (GPCR) family, to which ORs belong. Our analysis reveals an extraordinary diversity of natural variations in the olfactory gene repertoire between individuals and populations, with a significant number of changes occurring at the structurally conserved regions. A particular attention is paid to mutations in positions linked to the conserved GPCR activation mechanism that could imply phenotypic variation in the olfactory perception. An interactive web application (hORMdb, Human Olfactory Receptor Mutation Database) was developed for the management and visualization of this mutational dataset. Conclusion We performed topological annotations and population analysis of natural variants of human olfactory receptors and provide an interactive application to explore human OR mutation data. We envisage that the utility of this information will increase as the amount of available pharmacological data for these receptors grow. This effort, together with ongoing research in the study of genetic changes in other sensory receptors could shape an emerging sensegenomics field of knowledge, which should be considered by food and cosmetic consumer product manufacturers for the benefit of the general population.


Sign in / Sign up

Export Citation Format

Share Document