Conformational Flexibility and Structural Dynamics in GPCR-Mediated G Protein Activation: A Perspective

Abstract

Structure and dynamics of G proteins and their cognate receptors, both alone and in complex, are becoming increasingly accessible to experimental techniques. Understanding the conformational changes and timelines which govern these changes can lead to new insights into the processes of ligand binding and associated G protein activation. Experimental systems may involve the use of, or otherwise stabilize, non-native environments. This can complicate our understanding of structural and dynamical features of processes such as the ionic lock, Tryptophan toggle, and G protein flexibility. While elements in the receptor’s transmembrane helices and the C-terminal α5 helix of Gα undergo well defined structural changes, regions subject to conformational flexibility may be important in fine-tuning the interactions between activated receptors and G proteins. The pairing of computational and experimental approaches will continue to provide powerful tools to probe the conformation and dynamics of receptor-mediated G protein activation.

International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, Urotensin II–Related Peptide, and Their Receptor: From Structure to Function

“…The 3D arrangement of UT was also used (Kinney et al, 2002;Lavecchia et al, 2005;Lescot et al, 2008b) to determine the particular physicochemical requirements of the binding pocket of the receptor and help for the design of new nonpeptidic UT ligands. Although appealing, this approach remains complex because GPCRs are dynamic biomolecules exhibiting conformational changes upon activation (Preininger et al, 2013). Nevertheless, the 3D information might be very useful for understanding the binding process of existing leads, as shown by docking studies performed with the nonpeptidic UII agonist AC-7954 (Lavecchia et al, 2005) (Fig.…”

Bacterial chemoreceptor dynamics correlate with activity state and are coupled over long distances

“…These ideas have been largely supported by computational studies (2), although direct measurements also correlate dynamics with activity (1)(2)(3)(4). Nonetheless, we are only beginning to address the link between conformational heterogeneity and signal propagation in complex proteins.…”

“…chemotaxis | transmembrane signaling receptor | allostery | dynamics | adaptation T he ability of localized dynamics to modulate the function of transmembrane receptors is an emerging theme in signal transduction (1)(2)(3)(4). These ideas have been largely supported by computational studies (2), although direct measurements also correlate dynamics with activity (1)(2)(3)(4).…”

Structural Basis of G Protein-coupled Receptor-Gi Protein Interaction

“…Activation of CB 2 has been shown experimentally to produce coupling to G␣ i inhibitory protein (18 -20). Although a significant amount of information is available for GPCR-catalyzed activation of G proteins (21), many atomic level details concerning complex formation and signal transduction remain unanswered.…”