Allosteric Inhibition of G-Protein Coupled Receptor Oligomerization: Strategies and Challenges for Drug Development

Abstract

G-protein coupled receptors (GPCRs) mediate a large number of biological pathways and are major therapeutic targets. One of the most exiting phenomena of GPCRs is their ability to interact with other GPCRs. GPCRGPCR interactions, also known as GPCR oligomerization, may create various functional entities such as homo- and heterodimers and also form complex multimeric GPCR clusters. In many biological systems, GPCR-GPCR interactions are crucial for signal regulation. The interaction with other receptors results in allosteric modifications of GPCRs through conformational changes. Allosteric inhibition of GPCRs is considered an attractive strategy for drug development and does not involve targeting the orthosteric site. Understanding the nature of GPCR-GPCR interactions is mandatory for developing allosteric inhibitors. Studying GPCR-GPCR interactions is a challenging task and many methods have been developed to analyze these events. This review will highlight some of the methods developed to study GPCR-GPCR interactions and will describe pivotal studies that provided the basic understanding of the importance of GPCR oligomerization. We will also describe the significance of GPCR interaction networks for drug development. Recent studies will be reviewed to illustrate the use of state-of-the-art biophysical and spectroscopic methods for the discovery of GPCR oligomerization modulators.

The Endocannabinoid System as a Target in Cancer Diseases: Are We There Yet?

“…Kniazeff et al (2011) reviewed that dimer formation is a prerequisite for canonical receptor function in class C GPCRs, and Xue et al (2015) demonstrated that the mGluR2 dimer interface switches from TM4-TM5 in the inactive state to TM6-TM6 interactions in the active conformation, revealing a key step in class C GPCR activation. In the large subfamily A of GPCRs, although several receptors are able to operate as monomers (Chabre and le Maire, 2005; Ernst et al, 2007; Hanson et al, 2007; Whorton et al, 2007, 2008; Kuszak et al, 2009; Arcemisbéhère et al, 2010; Bayburt et al, 2011), experimental data have shown that most receptors could be expressed as a mixture of monomers and homodimers/oligomers (Teichmann et al, 2014; Vischer et al, 2015; Franco et al, 2016; Nemoto et al, 2016), and that oligomerization is necessary for the maturation of the receptor, its inclusion in the membrane and its function (Angers et al, 2000, 2002; Fotiadis et al, 2003; Herrick-Davis et al, 2006; Lopez-Gimenez et al, 2007; Han et al, 2009; Wade et al, 2011; Ng et al, 2013; Hurevich et al, 2014; Liste et al, 2015; Gahbauer and Böckmann, 2016; Lao et al, 2017; Jin et al, 2018). Fung et al (2009) reported receptor oligomers, mostly with tetrameric structure, of β2-adrenergic receptors after reconstitution into phospholipid vesicles.…”

Investigation of allosteric modulation mechanism of metabotropic glutamate receptor 1 by molecular dynamics simulations, free energy and weak interaction analysis

“…The mGlu 1 has been considered to be an important target of the known structure of class C GPCRs for structure-based drug design 19 . Due to the specific allosteric sites in the 7TM domain of mGlu 1 , negative allosteric modulators (NAM) can be designed based on the crystal structure or known NAM 3 20 21 . The cholesterols are considered as the lipid rafts to pack the lipids and membrane proteins tightly 22 .…”