Journal
CURRENT OPINION IN STRUCTURAL BIOLOGY
Volume 41, Issue -, Pages 247-254Publisher
CURRENT BIOLOGY LTD
DOI: 10.1016/j.sbi.2016.11.005
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Funding
- National Institute of General Medical Sciences [RO1-GM083118, U19-GM106990, RO1-GM068603]
- National Institutes of Drug Abuse [R21-031418]
- Michigan Diabetes Research and Training Center Grant, National Institute of Diabetes and Digestive and Kidney Diseases [P60DK-20572]
- University of Michigan Biological Sciences Scholars Program
- Pharmacological Sciences Training Program [T32GM007767]
- AHA Midwest Affiliate Predoctoral Fellowship [13PRE17110027]
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G protein-coupled receptors (GPCRs) respond to extracellular stimuli and interact with several intracellular binding partners to elicit cellular responses, including heterotrimeric G proteins. Recent structural and biophysical studies have highlighted the dynamic nature of GPCRs and G proteins and have identified specific conformational changes important for receptor mediated nucleotide exchange on G alpha. While domain separation within G alpha is necessary for GDP release, opening the inter-domain interface is insufficient to stimulate nucleotide exchange. Rather, an activated receptor promotes GDP release by allosterically disrupting the nucleotide-binding site via interactions with the G alpha N-termini and C-termini. Highlighting the allosteric nature of GPCRs, recent studies suggest that agonist binding alone poorly stabilizes an active conformation of several receptors. Rather, full stabilization of the receptor in an active state requires formation of the agonist-receptor-G protein ternary complex. In turn, nucleotide-free G alpha is able to stabilize conformational changes around the receptor's agonist-binding site to enhance agonist affinity.
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