The role of structural dynamics in GPCR‐mediated signaling

Abstract

G protein-coupled receptors (GPCRs) play critical roles in the regulation of human physiology in response to a wide array of different extracellular stimuli and thus represent one of the largest groups of therapeutic drug targets. Recent advances in the structural characterization of GPCRs in different conformations and in complex with G proteins and arrestins have provided important insights into the mechanism and function of GPCRs. However, in order to truly understand the molecular basis of the functional versatility of GPCRs, the structural snapshots obtained by X-ray crystallography or cryo-EM need to be complimented with information about the conformational dynamics of receptors and their signaling complexes. In the last decade, a combination of biophysical approaches and computational studies has been utilized to examine the molecular motions of GPCRs and their transducer complexes and how they are regulated by ligands of different efficacy and bias. These studies revealed that GPCRs are highly dynamic allosteric proteins that can sample multiple conformational states. Ligands with distinct signaling profiles not only impact the conformational landscape of GPCRs but also of the receptor-engaged G proteins and arrestins. The conformational dynamics of GPCRs and their signaling complexes and the ligand-dependent bias sampling of distinct functional states are important underlying principles behind the complex signaling behavior of GPCRs.

Intrathecal Injection of Ropivacaine Reduces Cervical Resistance in Late-Pregnant Rats

“…The activation of adrenergic receptors (which are approximately divided into α1, α2, and β receptors) requires the mediation of G protein to couple with the second messenger to produce a series of signal transduction and physiological effects. 24 , 25 In contrast to the effect of β receptors in increasing the concentration of cAMP in smooth muscle cells by coupling to Gs, α2 receptors couple with Gi, which can inhibit the activity of adenylate cyclase and reduce the synthesis of cAMP, thereby reducing MLCK activity inhibition with the result of smooth muscle cell contraction. 26–28 Some studies concerning the relationship between cervical tone and adrenergic receptors also support the abovementioned discussion.…”

The Many Faces of G Protein-Coupled Receptor 143, an Atypical Intracellular Receptor

“… 4) A coordinated conformational change upon ligand coupling of aromatic residues in TM6, also known as CWxP motif around a very conserved tryptophan (6.48) that leads to disruption of the ionic lock and outward movement of TM6 (called Rotamer Toggle Switch), while TM7 undergoes inward movement towards TM5 ( Weinstein, 2006 ; Hofmann et al, 2009 ; Nygaard et al, 2009 ; Holst et al, 2010 ; Standfuss et al, 2011 ; Trzaskowski et al, 2012 ; Valentin-Hansen et al, 2012 ; Tehan et al, 2014 ; Zhang et al, 2015 ; Venkatakrishnan et al, 2016 ; Plazinska et al, 2017 ; Eddy et al, 2018 ; Kaiser et al, 2018 ; Filipek, 2019 ); instead of CWxP, CWLS is found in GPR143 in the same position ( Ghosh et al, 2012 ). 5) The PIF motif comprising residues P5.50, I3.40 and F6.44 ( Ballesteros and Weinstein, 1995 ; Ishchenko et al, 2017 ; Schönegge et al, 2017 ; Kato et al, 2019 ; Hilger, 2021 ; Smith, 2021 ); the PIF motif is also not present in GPR143, only P5.50 itself is found. 6) The Na + -pocket at a conserved aspartic acid (2.50) ( Liu et al, 2012 ; Yuan et al, 2013 ; Zhang et al, 2013 ; Katritch et al, 2014 ; Eddy et al, 2018 ; Vickery et al, 2018 ; White et al, 2018 ; Ye et al, 2018 ; Chen S. et al, 2019 ; Filipek, 2019 ; Agasid et al, 2021 ); D2.50 important for Na + binding is also present in GPR143.…”

“…5) The PIF motif comprising residues P5.50, I3.40 and F6.44 ( Ballesteros and Weinstein, 1995 ; Ishchenko et al, 2017 ; Schönegge et al, 2017 ; Kato et al, 2019 ; Hilger, 2021 ; Smith, 2021 ); the PIF motif is also not present in GPR143, only P5.50 itself is found.…”

New Horizons in Structural Biology of Membrane Proteins: Experimental Evaluation of the Role of Conformational Dynamics and Intrinsic Flexibility

“…Antibody fragments have been instrumental in capturing these various conformations associated with a receptor's transition from an inactive to active state. A breakthrough application of antibody fragments has been in the field of GPCRs which are highly flexible and sample multiple conformations [156]. Cytochrome c oxidase with scFv was the first demonstrated co-crystallization of a membrane protein [157], since then several membrane proteins have been crystallized with antibody fragments scFv and Fab [147,149,[158][159][160][161][162].…”