Pancreatic ductal adenocarcinoma (PDAC) remains a dreadful disease with poor prognosis. While the prognosis of colorectal carcinoma (CRC) is better than that of PDAC, it still is the second-leading ...cause of cancer deaths worldwide. Recently, a (methyl)lanthionine-stabilized, highly receptor-specific agonist of galanin subtype 2 (GAL2) receptor inhibited the growth of GAL2 receptor-expressing patient-derived xenografts (PDX) of pancreatic cancer. Furthermore, a lanthionine-constrained agonist of angiotensin II type 2 (AT2) receptor inhibited PDX of colorectal cancer in mice. Stimulation of GAL2 receptor may modulate immune surveillance and inhibits PDAC via cell cycle inhibition and apoptosis. Consistent with GAL2 receptor-mediated tumor inhibition, for PDAC, survival is much higher for patients with high GAL2 receptor expression. Importantly, a (methyl)lanthionine-stabilized GAL2 receptor-specific agonist enhances expression of GAL2 receptor, not only in PDAC-PDX but also in healthy tissue indicating therapeutic and preventive potentials for GAL2 receptor agonists. AT2 receptor is interacting with four tumor suppressor proteins, Src homology phosphatase 1, Src homology phosphatase 2, Promyelocytic Leukemia Zinc Finger protein and Microtuble-Associated Scaffold Protein1, the latter also known as Angiotensin-II type 2 receptor-Interacting Protein. Pathways linked to these tumor suppressor proteins may enhance immune surveillance, prevent carcinogenesis, counter proliferation and stimulate apoptosis. Taken together, current data are prompting the hypothesis of a prophylactic treatment option with stable, specific and safe agonists of GAL2 receptor and AT2 receptor to prevent the emergence of pancreatic and colorectal cancer in individuals at risk.
Fully understanding the mechanisms of signaling proteins such as G protein-coupled receptors (GPCRs) will require the characterization of their conformational states and the pathways connecting those ...states. The recent crystal structures of the β
2
- and β
1
-adrenergic receptors in a nominally inactive state constituted a major advance toward this goal, but also raised new questions. Although earlier biochemical observations had suggested that these receptors possessed a set of contacts between helices 3 and 6, known as the ionic lock, which was believed to form a molecular switch for receptor activation, the crystal structures lacked these contacts. The unexpectedly broken ionic lock has raised questions about the true conformation(s) of the inactive state and the role of the ionic lock in receptor activation and signaling. To address these questions, we performed microsecond-timescale molecular dynamics simulations of the β
2
-adrenergic receptor (β
2
AR) in multiple wild-type and mutant forms. In wild-type simulations, the ionic lock formed reproducibly, bringing the intracellular ends of helices 3 and 6 together to adopt a conformation similar to that found in inactive rhodopsin. Our results suggest that inactive β
2
AR exists in equilibrium between conformations with the lock formed and the lock broken, whether or not the cocrystallized ligand is present. These findings, along with the formation of several secondary structural elements in the β
2
AR loops during our simulations, may provide a more comprehensive picture of the inactive state of the β-adrenergic receptors, reconciling the crystal structures with biochemical studies.
Markers of hyperactive central corticotropin releasing factor (CRF) systems and CRF‐related single nucleotide polymorphisms (SNPs) have been identified in patients with anxiety and depressive ...disorders. Designing more effective antagonists may now be guided by data showing that small molecules bind to transmembrane domains. Specifically, CRF1 receptor antagonists have been developed as novel anxiolytic and antidepressant treatments. Because CRF1 receptors become rapidly desensitized by G protein‐coupled receptor kinase (GRK) and β‐arrestin mechanisms in the presence of high agonist concentrations, neuronal hypersecretion of synaptic CRF alone may be insufficient to account for excessive central CRF neurotransmission in stress‐induced affective pathophysiology. In addition to desensitizing receptor function, GRK phosphorylation and β‐arrestin binding can shift a G protein‐coupled receptor (GPCR) to signal selectively via the extracellular signal‐regulated kinase/mitogen‐activated protein kinase (ERK‐MAPK) or Akt pathways independent of G proteins. Also, Epac‐dependent CRF1 receptor signaling via the ERK‐MAPK pathway has been found to potentiate brain‐derived neurotrophic factor (BDNF)‐stimulated TrkB signaling. Thus, genetic or acquired abnormalities in GRK and β‐arrestin function may be involved in the pathophysiology of stress‐induced anxiety and depression.
The serotonin receptor subtype 1A (5-HT1AR), one of the G-protein-coupled receptor (GPCR) family, has been implicated in several neurological conditions. Understanding the activation and inactivation ...mechanism of 5-HT1AR at the molecular level is critical for discovering novel therapeutics in many diseases. Recently there has been a growing appreciation for the role of external electric fields (EFs) in influencing the structure and activity of biomolecules. In this study, we used molecular dynamics (MD) simulations to examine conformational features of active states of 5-HT1AR and investigate the effect of an external static EF with 0.02 V/nm applied on the active state of 5-HT1AR. Our results showed that the active state of 5-HT1AR maintained the native structure, while the EF led to structural modifications in 5-HT1AR, particularly inducing the inward movement of transmembrane helix 6 (TM6). Furthermore, it disturbed the conformational switches associated with activation in the CWxP, DRY, PIF, and NPxxY motifs, consequently predisposing an inclination towards the inactive-like conformation. We also found that the EF led to an overall increase in the dipole moment of 5-HT1AR, encompassing TM6 and pivotal amino acids. The analyses of conformational properties of TM6 showed that the changed secondary structure and decreased solvent exposure occurred upon the EF condition. The interaction of 5-HT1AR with the membrane lipid bilayer was also altered under the EF. Our findings reveal the molecular mechanism underlying the transition of 5-HT1AR conformation induced by external EFs, which offer potential novel insights into the prospect of employing structure-based EF applications for GPCRs.
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•Electric field changed the conformation of 5-HT1AR.•Under the electric field, intracellular end of TM6 undergone an inward tilt to TM3.•Electric field rearranged conformational switches for the activation of 5-HT1AR.•The interaction of the membrane with 5-HT1AR was regulated by electric field.
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