ArticleJournal of molecular biology2008
Evolution of class-specific peptides targeting a hot spot of the Galphas subunit.
Article in Journal of molecular biology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 25 citations in OpenAlex.
- Post-Selection Methods for Analyzing mRNA Display Selections and Optimization of Hits.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Heterotrimeric G protein signaling without GPCRs: The Gα-binding-and-activating (GBA) motif.The Journal of biological chemistry · 2024Review
- Article
- Targeting Gαi/s Proteins with Peptidyl Nucleotide Exchange Modulators.ACS chemical biology · 2022Article
- Directing evolution of novel ligands by mRNA display.Chemical Society reviews · 2021Review
- Strategies towards Targeting Gαi/s Proteins: Scanning of Protein-Protein Interaction Sites To Overcome Inaccessibility.ChemMedChem · 2021Review
- DAPLE protein inhibits nucleotide exchange on GαThe Journal of biological chemistry · 2020Article
- A biochemical and genetic discovery pipeline identifies PLCδ4b as a nonreceptor activator of heterotrimeric G-proteins.The Journal of biological chemistry · 2018Article
- RasIns: Genetically Encoded Intrabodies of Activated Ras Proteins.Journal of molecular biology · 2017Article
- Evolutionary Conservation of a GPCR-Independent Mechanism of Trimeric G Protein Activation.Molecular biology and evolution · 2016Article
- Daple is a novel non-receptor GEF required for trimeric G protein activation in Wnt signaling.eLife · 2015Article
- Serum stable natural peptides designed by mRNA display.Scientific reports · 2014Article
- Plucking the high hanging fruit: a systematic approach for targeting protein-protein interactions.Bioorganic & medicinal chemistry · 2013Article
- Crucial roles of Glu60 in human neuroglobin as a guanine nucleotide dissociation inhibitor and neuroprotective agent.PloS one · 2013Article
- IQcat: multiplexed protein quantification by isoelectric QconCAT.Proteomics · 2012Article
- Expanding the conformational selection paradigm in protein-ligand docking.Methods in molecular biology (Clifton, N.J.) · 2012Article
- G Protein binding sites on Calnuc (nucleobindin 1) and NUCB2 (nucleobindin 2) define a new class of G(alpha)i-regulatory motifs.The Journal of biological chemistry · 2011Article
- Selection of proteins with desired properties from natural proteome libraries using mRNA display.Nature protocols · 2011Article
- Advantages of mRNA display selections over other selection techniques for investigation of protein-protein interactions.Expert review of proteomics · 2011Review
- Quantitative specificity-based display library screening identifies determinants of antibody-epitope binding specificity.Protein science : a publication of the Protein Society · 2009Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
The four classes of heterotrimeric G-protein alpha subunits act as molecular routers inside cells, gating signals based on a bound guanosine nucleotide (guanosine 5'-triphosphate versus guanosine 5'-diphosphate). Ligands that specifically target individual subunits provide new tools for monitoring and modulating these networks, but are challenging to design due to the high sequence homology and structural plasticity of the Galpha-binding surface. Here we have created an mRNA display library of peptides based on the short Galpha-modulating peptide R6A-1 and selected variants that target a convergent protein-binding surface of Galphas.guanosine 5'-diphosphate. After selection/evolution, the most Galphas-specific peptide, Galphas(s)-binding peptide (GSP), was used to design a second-generation library, resulting in several new affinity- and selectivity-matured peptides denoted as mGSPs. The two-step evolutionary walk from R6A-1 to mGSP-1 resulted in an 8000-fold inversion in binding specificity, altered seven out of nine residues in the starting peptide core, and incorporated both positive and negative design steps. The resulting mGSP-1 peptide shows remarkable selectivity and affinity, exhibiting little or no binding to nine homologous Galpha subunits or human H-Ras, and even discriminates the Galphas splice variant Galphas(l). Selected peptides make specific contacts with the effector-binding region of Galpha, which may explain an interesting bifunctional activity observed in GSP. Overall, our work demonstrates a design of simple, linear, highly specific peptides that target a protein-binding surface of Galphas and argues that mRNA display-based selection/evolution is a powerful route for targeting protein families with high class specificity and state specificity.
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Registered trials
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.