ArticleThe Journal of biological chemistry2014
A conserved phenylalanine as a relay between the α5 helix and the GDP binding region of heterotrimeric Gi protein α subunit.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed.
- Article
- The Enigmatic Conserved Q134-F135-N137 Triad in SARS-CoV-2 Spike Protein: A Conformational Transducer?Biomolecules · 2026Review
- Article
- G Protein Activation Occurs via a Largely Universal Mechanism.The journal of physical chemistry. B · 2024Article
- Mapping the conformational landscape of the stimulatory heterotrimeric G protein.Nature structural & molecular biology · 2023Article
- The Conformational Dynamics of Heterotrimeric G Proteins During GPCR-Mediated Activation.Sub-cellular biochemistry · 2022Review
- Article
- β2-adrenoceptor ligand efficacy is tuned by a two-stage interaction with the Gαs C terminus.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Cryo-EM structure of an activated GPCR-G protein complex in lipid nanodiscs.Nature structural & molecular biology · 2021Article
- Delineation of molecular determinants for FR900359 inhibition of GThe Journal of biological chemistry · 2020Article
- Structural basis for GPCR-independent activation of heterotrimeric Gi proteins.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Conformational plasticity of the intracellular cavity of GPCR-G-protein complexes leads to G-protein promiscuity and selectivity.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Assembly of a GPCR-G Protein Complex.Cell · 2019Article
- Structures of the M1 and M2 muscarinic acetylcholine receptor/G-protein complexes.Science (New York, N.Y.) · 2019Article
- A New Multisystem Disorder Caused by the Gαs Mutation p.F376V.The Journal of clinical endocrinology and metabolism · 2019Article
- Recent advances in computational studies of GPCR-G protein interactions.Advances in protein chemistry and structural biology · 2019Review
- Rules of Engagement: GPCRs and G Proteins.ACS pharmacology & translational science · 2018Review
- Comparative structural dynamic analysis of GTPases.PLoS computational biology · 2018Article
- Structure of the µ-opioid receptor-GNature · 2018Article
- Tracing the evolution of the heterotrimeric G protein α subunit in Metazoa.BMC evolutionary biology · 2018Article
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Authors and funding
6 authors.
Funding
Abstract
G protein activation by G protein-coupled receptors is one of the critical steps for many cellular signal transduction pathways. Previously, we and other groups reported that the α5 helix in the G protein α subunit plays a major role during this activation process. However, the precise signaling pathway between the α5 helix and the guanosine diphosphate (GDP) binding pocket remains elusive. Here, using structural, biochemical, and computational techniques, we probed different residues around the α5 helix for their role in signaling. Our data showed that perturbing the Phe-336 residue disturbs hydrophobic interactions with the β2-β3 strands and α1 helix, leading to high basal nucleotide exchange. However, mutations in β strands β5 and β6 do not perturb G protein activation. We have highlighted critical residues that leverage Phe-336 as a relay. Conformational changes are transmitted starting from Phe-336 via β2-β3/α1 to Switch I and the phosphate binding loop, decreasing the stability of the GDP binding pocket and triggering nucleotide release. When the α1 and α5 helices were cross-linked, inhibiting the receptor-mediated displacement of the C-terminal α5 helix, mutation of Phe-336 still leads to high basal exchange rates. This suggests that unlike receptor-mediated activation, helix 5 rotation and translocation are not necessary for GDP release from the α subunit. Rather, destabilization of the backdoor region of the Gα subunit is sufficient for triggering the activation process.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.