ArticleProceedings of the National Academy of Sciences of the United States of America2015
Comprehensive analysis of heterotrimeric G-protein complex diversity and their interactions with GPCRs in solution.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 55 citations in OpenAlex.
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- Mapping the conformational landscape of the stimulatory heterotrimeric G protein.Nature structural & molecular biology · 2023Article
- A Vaccinia-based system for directed evolution of GPCRs in mammalian cells.Nature communications · 2023Article
- Community guidelines for GPCR ligand bias: IUPHAR review 32.British journal of pharmacology · 2022Review
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- Every Detail Matters. That Is, How the Interaction between Gα Proteins and Membrane Affects Their Function.Membranes · 2021Review
- Cryo-EM structure of an activated GPCR-G protein complex in lipid nanodiscs.Nature structural & molecular biology · 2021Article
- iGIST-A Kinetic Bioassay for Pertussis Toxin Based on Its Effect on Inhibitory GPCR Signaling.ACS sensors · 2020Article
- Minute-scale persistence of a GPCR conformation state triggered by non-cognate G protein interactions primes signaling.Nature communications · 2019Article
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Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Agonist binding to G-protein-coupled receptors (GPCRs) triggers signal transduction cascades involving heterotrimeric G proteins as key players. A major obstacle for drug design is the limited knowledge of conformational changes upon agonist binding, the details of interaction with the different G proteins, and the transmission to movements within the G protein. Although a variety of different GPCR/G protein complex structures would be needed, the transient nature of this complex and the intrinsic instability against dissociation make this endeavor very challenging. We have previously evolved GPCR mutants that display higher stability and retain their interaction with G proteins. We aimed at finding all G-protein combinations that preferentially interact with neurotensin receptor 1 (NTR1) and our stabilized mutants. We first systematically analyzed by coimmunoprecipitation the capability of 120 different G-protein combinations consisting of αi1 or αsL and all possible βγ-dimers to form a heterotrimeric complex. This analysis revealed a surprisingly unrestricted ability of the G-protein subunits to form heterotrimeric complexes, including βγ-dimers previously thought to be nonexistent, except for combinations containing β5. A second screen on coupling preference of all G-protein heterotrimers to NTR1 wild type and a stabilized mutant indicated a preference for those Gαi1βγ combinations containing γ1 and γ11. Heterotrimeric G proteins, including combinations believed to be nonexistent, were purified, and complexes with the GPCR were prepared. Our results shed new light on the combinatorial diversity of G proteins and their coupling to GPCRs and open new approaches to improve the stability of GPCR/G-protein complexes.
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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.