Investigation of ECD conformational transition mechanism of GLP-1R by molecular dynamics simulations and Markov state model

Abstract

As a member of the class B G protein-coupled receptors (GPCRs), the glucagon-like peptide-1 (GLP-1) can regulate the blood glucose level by binding to the glucagon-like peptide-1 receptor (GLP-1R).

Differential GLP-1R binding and activation by peptide and non-peptide agonists

“…The importance of the interaction between the far ECD and ECL3 for maintaining receptor quiescence is supported by mutagenesis and biochemical studies with GLP-1R and the related GCGR that reveal loss of this interaction can reduce the barrier to activation, or engender constitutive activity in the case of the GCGR (Wu et al, 2020;Yang et al, 2015;Yin et al, 2016;Zhao et al, 2016). Nonetheless, molecular dynamics simulations indicate that the ECD is dynamic and can transiently, partially or fully, disengage from the receptor core and this is likely key to both peptide and small molecule binding (Wu et al, 2020;Yang et al, 2015;Zhang et al, 2019;.…”

Conformation Transition of Intracellular Part of Glucagon Receptor in Complex With Agonist Glucagon by Conventional and Accelerated Molecular Dynamics Simulations

“…In the previous reports, the MD simulations indicate that the extracellular domain (ECD) of apo-GCGR can be in open or closed state for elucidating glucagon binding mechanism (Yang et al, 2015). The similar phenomena of closed or open ECD domain also happen in apo-GLP-1R, which is studied by MD simulations and the Markov state model (Zhang et al, 2019). These scientific researches give a computational model for studying the two-domain binding mechanism of class B GPCRs.…”

New Insights into Beta-Cell GLP-1 Receptor and cAMP Signaling

“…Previous studies have shown that alpha cells, especially those at earlier stages of differentiation as well as alpha progenitor cells, might be the precursors of beta cells. Treatment with GLP-1 in rats exposed to a single high-dose of streptozotocin (STZ) to induce beta cell death results in increases in cell populations positive for both insulin and glucagon (GCG), suggesting that GLP-1R signaling might promote beta cell neogenesis by the trans-differentiation of alpha cells [31]. The proposed mechanism involves the regulation of the PI3K/Akt/FOXO1 pathway, resulting in increased pancreatic and duodenal homeobox 1 (Pdx1) and MafA expression but decreased MafB expression.…”

“…Advances in recent years include the application of concepts such as signal bias, allosteric modulation, dual agonism and the study of polymorphic receptor variants to the GLP-1R (for a summary of past investigations, see [6]). Additional recent areas of research include spatial compartmentalization of cAMP signaling as well as domain (ECD) by molecular dynamics simulations and Markov state modeling [31] has shown that the ECD of the GLP-1R adopts a closed conformation in the GLP-1-bound state and opens in the GLP-1-unbound apo-state of the receptor. Using a combination of alaninescanning mutagenesis and pharmacological quantification of the effects of mutations on peptide binding affinity and downstream signaling, key elements of the GLP-1R ECD involved in biased signaling responses engaged in a ligand-dependent manner have been identified [32].…”