Thomas P. Sakmar on how the molecular studies of rhodopsin paved the way to understanding #GPCRs Be sure to subscribe

November 2021 "So proud and grateful to receive honorary doctorate yesterday from Karolinska Institute and celebrate with my family in Stockholm." Read more at the source #DrGPCR #GPCR #IndustryNews

Bryan Roth, Peter Gmeiner, and Thomas P. Sakmar this week. For Dr.

Thomas P. Sakmar and his team used 'bioluminescence resonance energy transfer to measure cell-surface expression

Thomas P. Sakmar, Debbie L. Hay, Lukas Grätz, and more.

September 2022 "Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) lipids have been shown to stabilize an active conformation of class A G-protein coupled receptors (GPCRs) through a conserved binding site, not present in class B GPCRs. For class B GPCRs, previous molecular dynamics (MD) simulation studies have shown PI(4,5)P2 interacting with the Glucagon receptor (GCGR), which constitutes an important target for diabetes and obesity therapeutics. In this work, we applied MD simulations supported by native mass spectrometry (nMS) to study lipid interactions with GCGR. We demonstrate how tail composition plays a role in modulating the binding of PI(4,5)P2 lipids to GCGR. Specifically, we find the PI(4,5)P2 lipids to have a higher affinity toward the inactive conformation of GCGR. Interestingly, we find that in contrast to class A GPCRs, PI(4,5)P2 appear to stabilize the inactive conformation of GCGR through a binding site conserved across class B GPCRs but absent in class A GPCRs. This suggests differences in the regulatory function of PI(4,5)P2 between class A and class B GPCRs." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 "In the Wnt-β-catenin pathway, Wnt binding to Frizzled (Fzd) and LRP5 or LRP6 (LRP5/6) co-receptors inhibits the degradation of the transcriptional coactivator β-catenin by recruiting the cytosolic effector Dishevelled (Dvl). Polymerization of Dvl at the plasma membrane recruits the β-catenin destruction complex, enabling the phosphorylation of LRP5/6, a key step in inhibiting β-catenin degradation. Using purified Fzd proteins reconstituted in lipid nanodiscs, we investigated the factors that promote the recruitment of Dvl to the plasma membrane. We found that the affinity of Fzd for Dvl was not affected by Wnt ligands, in contrast to other members of the GPCR superfamily for which the binding of extracellular ligands affects the affinity for downstream transducers. Instead, Fzd-Dvl binding was enhanced by increased concentration of the lipid PI(4,5)P2, which is generated by Dvl-associated lipid kinases in response to Wnt and which is required for LRP5/6 phosphorylation. Moreover, binding to Fzd did not promote Dvl DEP domain dimerization, which has been proposed to be required for signaling downstream of Fzd. Our findings suggest a positive feedback loop in which Wnt-stimulated local PI(4,5)P2 production enhances Dvl recruitment and further PI(4,5)P2 production to support Dvl polymerization, LRP5/6 phosphorylation, and β-catenin stabilization." Read more at the source #DrGPCR #GPCR #IndustryNews

Expression "P-glycoprotein (P-gp) is a key component of the intestinal epithelium playing a pivotal secondary bile acids, produced by the intestinal microbiome, potentiate the induction of functional P-gp We now aim to determine the molecular mechanism by which this functional microbiome output regulates P-gp combination discovered a unique transcriptional program involving multiple pathways that converge on P-gp on a sophisticated signaling network directed by intestinal microbial metabolites that orchestrate P-gp

clinical parameters such as alpha-fetoprotein and tumor grade in the HCC patients; (c) besides HCC (p was found to be an important factor for survival in four other cancers (clear renal cell carcinoma: p < 0.001, lung adenocarcinoma: p = 0.004, mesothelioma: p = 0.039, ovarian serous cystadenocarcinoma: p = 0.048); (d) RGS20 was found to be significantly associated with some tumor-related signaling pathways

2016) where O-glycosylation contributes to the differential binding to CC or CX3C chemokine (Casarosa P phosphosulfate (PAPS) donor to the hydroxyl group of a tyrosine residue of the protein chain (Seibert C and Sakmar sites in their N-termini that mediate ligand binding and signaling (Bannert N et al. 2001; Casarosa P glycosulfo peptide analogue GSnP-6 displays nanomolar affinity and promising potential for blocking PSGL-1/P-selectin

Cell, 1997. 89(2): p. 251-61. https://pubmed.ncbi.nlm.nih.gov/9108480/ 2. Front Mol Neurosci, 2020. 13: p. 5. https://pubmed.ncbi.nlm.nih.gov/32038168/ 3. Cell, 2021. 184(4): p. 931-942.e18. https://pubmed.ncbi.nlm.nih.gov/33571431/ 6. J Neurosci, 2019. 39(42): p. 8291-8304. https://pubmed.ncbi.nlm.nih.gov/31308097/ 8. Genomics, 2021. 113(4): p. 2134-2144. https://pubmed.ncbi.nlm.nih.gov/33845140/

of patients showed high GPER expression and significant correlation with the mRNA subtype of TNBC (P  = 0.001), total metastatic events (P = 0.019) and liver metastasis (P = 0.011). interval of 67.1 months, a significant trend towards reduced distant metastasis-free survival (DMFS) (P 

and an analysis using quantitative PCR showed that it was expressed at all developmental stages of P. of double-stranded RNA in an RNA interference assay indicated that PxOctβ3 regulates development in P. This study demonstrated the pharmacological properties and functions of PxOctβ3 in P. xylostella, thus

., Casarosa, P., Chae, P. S., Devree, B. T., Rosenbaum, D. M., Thian, F. S., Kobilka, T. M., Manglik, A., Hu, J., Hu, K., Eitel, K., Hübner, H., Pardon, E., Valant, C., Sexton, P. C., Gmeiner, P., Steyaert, J., Weis, W. I., Garcia, K. C., Wess, J., & Kobilka, B. K. (2013). D., Tworak, A., Watanabe, K., Pardon, E., Steyaert, J., Kandori, H., Katayama, K., Kiser, P.

biosensors reveals distinct conformational signatures of β-arrestin1 and 2 when bound to active PTH1R (P-R Here, we show differences between conformational changes that are induced by P-R* or R* receptor states

P. (2009). Sustained cyclic AMP production by parathyroid hormone receptor endocytosis. https://doi.org/10.1210/en.2015-1945 Irannejad, R., Pessino, V., Mika, D., Huang, B., Wedegaertner, P. I., Gerrikagoitia, I., Suarez, J., Rodríguez De Fonseca, F., Puente, N., Marsicano, G., & Grandes, P. Frontiers in physiology, 7, 476. https://doi.org/10.3389/fphys.2016.00476 Insel, P. P., Lowy, A. M., & Murray, F. (2018).

The fission yeast Schizosaccharomyces pombe has two mating types, Plus (P) and Minus (M). Here, we investigated the stringency of the two GPCRs, Mam2 and Map3, for their respective pheromones, P-factor

FLNA absence reduced the basal number of hetero-dimers (-36.8 ± 6.3% reduction of PLA events in M2, P both A7 and M2 (+20.0 ± 11.8% and +44.1 ± 16.3% increase of PLA events in A7 and M2, respectively, P

. -11.6 placebo, p<0.0001) at Week 5 (Cohen’s d effect size of 0.61).

., Gmeiner, P., Kobilka, B. K., Hildebrand, P. W., & Skiniotis, G. (2023).

Embo j, 2012. 31(6): p. 1364-78. 2. Xiao, P., et al., Tethered peptide activation mechanism of the adhesion GPCRs ADGRG2 and ADGRG4. Nature, 2022. 604(7907): p. 628-630. 7.

Associated with Huntington Disease "Highly Statistically Significant Reduction in Chorea Movements (p

bioinformatics tools offer the potential to explore larger portions of the β-arrestin interactome (Crépieux, P. with overlapping sites may experience mutually exclusive binding due to steric hindrance (Crépieux, P.

and TM7 on the other hand, form possible dimerization interfaces (Ploier, B. et al. 2016; Dijkman, P.

challenge in the Dahl SS rat GPCRs in Neuroscience Neurokinin-2 receptor negatively modulates substance P

They also showed higher protein levels of phospho-glycogen synthase kinase-3β (p-GSK3β), as well as total

Toxicol. 52, 179–197. https://doi.org/10. 1146/annurev.pharmtox.010909.105800 Tsao, P.

towards previously established chemical space, limiting their ability to identify truly novel chemotypes”(Thomas