G-protein-coupled receptors (GPCRs) transduce diverse signals into the cell by coupling to one or several Gα subtypes. Of the 16 Gα subtypes in human cells, Gα and Gα belong to the G subfamily and are reported to be functionally different. Notably, certain GPCRs display selective coupling to either Gα or Gα, highlighting their significance in various cellular contexts. However, the structural basis underlying this selectivity remains unclear. Here, using a Gα-coupled designer receptor exclusively activated by designer drugs (DREADD; GD) as a model system, we identified residues in the α5 helix and the receptor that collaboratively determine Gα-vs-Gα selectivity. Residue-swapping experiments showed that GD distinguishes differences between Gα and Gα in the positions G.H5.09 and G.H5.23 in the α5 helix. Molecular dynamics simulations observed that I378 in Gα interacts with N103, S169 and Y176 in GD, while H364 in Gα interact with Q264 in GD. Screening of mutations at these positions in GD identified GD mutants that enhanced coupling with Gα and to an even greater extent with Gα. Combined mutations, most notably the dual Y176H and Q264R mutant, further enhanced Gα coupling, thereby serving as a potential Gα-DREADD. Such novel Gα-DREADD may be useful in future efforts to develop drugs that target Gα signaling as well as to identify their therapeutic indications.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11096383 | PMC |
| http://dx.doi.org/10.1038/s41598-024-61506-4 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Digital microfluidic platform for dried blood spot newborn screening of lysosomal storage diseases in Campania region (Italy): Findings from the first year pilot project.
Mol Genet Metab
December 2024
Department of Molecular Medicine and Medical Biotechnology, Medical School, University of Naples Federico II, 80131 Naples, Italy; CEINGE-Biotecnologie Avanzate Franco Salvatore s.c.ar.l., 80145 Naples, Italy. Electronic address:
Background: Newborn screening (NBS) is a simple, non-invasive test that allows for the early identification of genetic diseases within the first days of a newborn's life. The aim of NBS is to detect potentially fatal or disabling conditions in newborns as early as possible, before the onset of disease symptoms. Early diagnosis enables timely treatments and improves the quality of life for affected patients.
View Article and Find Full Text PDFInteraction study of the effects of environmental exposure and gene polymorphisms of inflammatory and immune-active factors on chronic obstructive pulmonary disease.
Respir Res
January 2025
Center for Endemic Disease Control, Chinese Center for Disease Control and Prevention, Center for Chronic Disease Prevention and Control, Harbin Medical University, Harbin, 150081, People's Republic of China.
Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease, influenced by both environmental and genetic factors. Single nucleotide polymorphism (SNP) in the human genome may influence the risk of developing COPD and the response to treatment. We assessed the effects of gene polymorphism of inflammatory and immune-active factors and gene-environment interaction on risk of COPD in middle-aged and older Chinese individuals.
View Article and Find Full Text PDFtRNA thiolation optimizes appressorium-mediated infection by enhancing codon-specific translation in Magnaporthe oryzae.
Nucleic Acids Res
January 2025
National Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China.
Thiolation, a post-transcriptional modification catalyzed by Uba4-Urm1-Ncs2/Ncs6 pathway in three specific transfer RNAs (tRNAs), is conserved from yeast to humans and plays an important role in enhancing codon-anticodon interaction and translation efficiency. Yet, except for affecting effector secretion, its roles in plant pathogenic fungi are not fully understood. Here, we used Magnaporthe oryzae as a model system to illustrate the vital role of s2U34 modification on the appressorium-mediated virulence.
View Article and Find Full Text PDFChallenges in multinational rare disease clinical studies during COVID-19: regulatory assessment of cipaglucosidase alfa plus miglustat in adults with late-onset Pompe disease.
J Neurol
January 2025
John Walton Muscular Dystrophy Research Centre, Newcastle University, Newcastle-upon-Tyne, UK.
PROPEL (ATB200-03; NCT03729362) compared the efficacy and safety of cipaglucosidase alfa plus miglustat (cipa + mig), a two-component therapy for late-onset Pompe disease (LOPD), versus alglucosidase alfa plus placebo (alg + pbo). The primary endpoint was change in 6-min walk distance (6MWD) from baseline to week 52. During PROPEL, COVID-19 interrupted some planned study visits and assessment windows, leading to delayed visits, make-up assessments for patients who missed ≥ 3 successive infusions before planned assessments at weeks 38 and 52, and some advanced visits (end-of-study/early-termination visits).
View Article and Find Full Text PDFPredicting the phenotype of Pompe Disease from features of GAA variants.
Eur J Hum Genet
January 2025
Greg Marzolf Jr. Muscular Dystrophy Center, University of Minnesota Medical School, Minneapolis, MN, USA.
As the management of Pompe disease depends on whether an individual has infantile onset Pompe disease (IOPD) or late onset Pompe disease (LOPD), the question of whether the phenotype can be predicted from specific pathogenic variants is becoming increasingly important. We reviewed published cases of Pompe disease in which IOPD versus LOPD and pathogenic GAA variants were assigned for specific individuals. We then compared variant types and locations versus phenotypes.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!