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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

Tom Sakmar and Dr. Modulator for Non-Addictive Pain Relief   A Cell-Permeable Fluorescent Probe Illuminates Early PI(4,5)P₂

This Week’s Highlights: Celebrating Excellence: Hyoungjun Ham , Yamina Berchiche , Thomas Sakmar , Vladimir mutations in a G protein identify signaling cross-talk in T cells Victoria Saca , Colin Burdette , and Thomas Sakmar for their excellent study on GPCR Biosensors to Study Conformational Dynamics and Signaling

Tom Sakmar points to a largely overlooked mechanism  in disease: autoantibodies that don’t block receptors A New Role for GPCRs in Disease Sakmar highlights how endothelial cells, which express a wide array of “Some of these antibodies actually activate the receptor and cause pathological signaling.” — Tom Sakmar Sakmar and Kotliar’s system is multiplexed and scalable , able to test hundreds of interactions from

Tom Sakmar didn’t set out to map GPCR-RAMP interactions across hundreds of receptors. In fact, it all began with a phone call (from Bruce Merrifield, no less) encouraging Sakmar to work on A Long-Term Obsession, Reframed Sakmar’s lab had been focused on the secretin receptor family  for decades “The beauty of multiplexing is that you can do many things with one pot of samples.” — Tom Sakmar Enter

Sakmar reflects on a generational shift in training. Building for the Future The Sakmar lab built a system to meet that need: Dual-epitope tagged constructs This delivers all three.” — Tom Sakmar A Use Case for Every Angle Beyond RAMPs, this platform can study

for their work on GPCR gene variants and human genetic disease Ilana Kotliar , Thomas Sakmar , et al.

Explore the partnership Multiplexing GPCR Discovery - Sakmar Lab’s Toolkit Goes Public The latest podcast Tom Sakmar, Emily Lorenzen, and Ilana Kotliar about creating a multiplex system with DUET-tagged constructs

Nat Rev Neurosci, 2001. 2 (4): p. 274-86. 3.          Pharmacol Rev, 2016. 68 (4): p. 954-1013. 6.          Nature Communications, 2024. 15 (1): p. 4390. 7.          Mol Pharmacol, 2012. 81 (3): p. 309-18. 9.          Chem Rev, 2017. 117 (1): p. 111-138.

Annu Rev Biochem, 1987. 56: p. 615-49. 2.      Cell, 2020. 182(3): p. 770-785.e16. 4.      Nature, 2020. 577(7790): p. 432-436. 6.      Nat Methods, 2005. 2(3): p. 177-84. 7.      Nat Protoc, 2006. 1(1): p. 337-45. 15.   

-A., Thomas, T., Nguyen, T. D., Muñoz, L. L., Gregory, K. J., White, P. J., Sexton, P.

Nat Rev Drug Discov, 2013. 12 (3): p. 205-16. 2.          Cell Metab, 2018. 27 (4): p. 740-756. 3.          Cell, 2016. 165 (7): p. 1632-1643. 6.          Nat Commun, 2015. 6 : p. 8918. 7.          Endocr Rev, 2023. 44 (3): p. 492-517. 8.         

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

.; Popov, P.; Benchama, O.; Zvonok, N.; Locke, K.; Qu, L.; Han, G. W.; Iyer, M. V.; Van Der Stelt, M.; Pacher, P.; Gertsch, J.; Ullmer, C.; McCormick, P. J.; Oddi, S.; Spaink, H. P.; Maccarrone, M.; Veprintsev, D. B.; Carreira, E. M.; Grether, U.; Nazaré, M. -P. -F.; Farce, A.; Chavatte, P.; Poupaert, J. H.; Lambert, D. M.; Depreux, P.; Hénichart, J.-P.

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

phosphorylation of the G protein subunit Gαi at specific residues within three strategic hotspots: the P Key findings include: Phosphorylation Hotspots: P Loop (Ser44, Ser47, Thr48): Impairs ligand-stimulated Signaling Pathway Segregation: Phosphorylation events in the interdomain cleft and P loop uncouple G J., Ghassemian, M., Kufareva, I., & Ghosh, P. (2024).

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

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

J., Pardon, E., Casarosa, P., Chae, P. S., Devree, B. T., Rosenbaum, D. M., Thian, F. 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.

Proc Natl Acad Sci U S A, 2020. 117(35): p. 21723-21730. 2.      Proceedings of the National Academy of Sciences, 2017. 114(14): p. 3756-3761. 3.      Mol Pharmacol, 2017. 91(5): p. 533-544.

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).