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ispartof: European Company and Financial Law Review vol:17 issue:2 pages:125-128 status: published

The human glucagon receptor, GCGR, belongs to the class B G-protein-coupled receptor family and plays a key role in glucose homeostasis and the pathophysiology of type 2 diabetes. Here we report the 3.0 Å crystal structure of full-length GCGR containing both the extracellular domain and transmembrane domain in an inactive conformation. The two domains are connected by a 12-residue segment termed the stalk, which adopts a β-strand conformation, instead of forming an α-helix as observed in the previously solved structure of the GCGR transmembrane domain. The first extracellular loop exhibits a β-hairpin conformation and interacts with the stalk to form a compact β-sheet structure. Hydrogen-deuterium exchange, disulfide crosslinking and molecular dynamics studies suggest that the stalk and the first extracellular loop have critical roles in modulating peptide ligand binding and receptor activation. These insights into the full-length GCGR structure deepen our understanding of the signalling mechanisms of class B G-protein-coupled receptors.

Issuers are under an obligation to disclose inside information as soon as possible according to the disclosure regime in Art 17 of the Market Abuse Regulation (MAR). The article explores what and when an issuer must disclose. The threshold for determining what constitutes inside information is low, which ensures an early application of the insider dealing regime of MAR Art 8. The low threshold includes information of an intermediate nature, which is often uncertain and consequently likely to mislead the public if disclosed. However, the disclosure regime allows for delay to avoid this.

A protocol was defined which utilised peptides as probes for the characterisation of reversed phase chromatography peptide separation systems. These peptide probes successfully distinguished between differing stationary phases through the probe's hydrophobic, electrostatic, hydrogen bonding and aromatic interactions with the stationary phase, in addition, to more subtle interactions such as the phase's ability to separate racemic or isomeric probes. The dominating forces responsible for the chromatographic selectivity of peptides appear to be hydrophobic as well as electrostatic and polar in nature. This highlights the need for other types of stationary phase ligands with possibly mixed mode functionalities / electrostatic / polar interactions for peptide separations rather than the hydrophobic ligands which dominate small molecule separations. Selectivity differences are observed between phases, but it appears that it is the accessibility differences between these phases which play a crucial role in peptide separations i.e. accessibility to silanols, the hydrophobic acetonitrile / ligand layer or a thin adsorbed water layer on the silica surface.

Gennemgang og analyse af gældende børeretlig regulering

The pharmacological potential of Calcitonin gene-related peptide (CGRP) beyond vasodilation is not completely understood and studies are limited by the potent vasodilatory effect and the short half-life of CGRP. In particular, the effects of CGRP on metabolic diseases are not clarified. A peptide analogue of the α form of CGRP (αAnalogue) with prolonged half-life (10.2 ± 0.9h) in rodents was synthesised and used to determine specific metabolic effects in 3 rodent models; normal rats, diet-induced obese rats and the Leptin deficient mouse model (ob/ob mice). The αAnalogue (100 nmol/kg) induced elevated energy expenditure and reduced food intake after single dosing in normal rats. In addition, the αAnalogue increased levels of circulating Glucagon-Like Peptide-1 (GLP-1) by >60% and a specific concentration dependent CGRP-induced GLP-1 secretion was verified in a murine L-cell line. Two weeks treatment of the type 2 diabetic ob/ob mice with the αAnalogue caused reduction in fasting insulin levels (199 ± 36 pM vs 332 ± 68 pM) and a tendency to reduce fasting blood glucose (11.2 ± 1.1mM vs 9.5 ± 0.5mM) and % glycosylated haemoglobin (HbA1c) (5.88 ± 0.17 vs 5.12 ± 0.24), demonstrating a potential anti-diabetic effect. Furthermore, two weeks treatment of diet-induced obese rats with the αAnalogue caused reduction in food intake and a significant decline in body weight (3.6 ± 1.9 gvs. -36 ± 1.1g). We have demonstrated that long-acting CGRP analogues may have a therapeutic potential for the treatment of type 2 diabetes through positive metabolic effects and effect on GLP-1 secretion.

This paper represents a lecture delivered at the conference, The Takeovers Directive – Ten Years On, held on 22 April 2016 by Trinity College Dublin. The case against the mandatory bid rule in EU law is well-known by now and all the arguments have been heard before. It is an exercise usually done in vain, because the rule is safely embedded in the Takeover Directive, which is a Pandora’s box nobody wants to open and renegotiate. Most spectators are disinterested and, when pressed for an opinion, tend to offer a favourable view of it for differing reasons of self-interest. Arguing against the rule is the modern legal equivalent of tilting at windmills, except that the rule is not an imaginary evil but represents some very real problems that are characteristic of what is wrong with EU law today.

The crystal structure of the full-length glucagon receptor in complex with a glucagon analogue NNC1702 reveals how the peptide ligand interacts with its target and shows the conformational changes required for receptor activation. The glucagon receptor is a class B G-protein-coupled receptor with an important role in glucose homeostasis. Activation of this receptor triggers the release of glucose, making it an important target for the treatment of type 2 diabetes. Beili Wu and colleagues now report the crystal structure of the full-length glucagon receptor bound to a glucagon analogue and a partial agonist, NNC1702. The 3.0 A resolution of the structure provides key insights into how the peptide ligand interacts with its target and the conformational changes involved in the initial stages of activation. The structural data is reinforced by using double electron–electron resonance (DEER) spectroscopy, which demonstrates the extent of rearrangement that is involved in accommodating the glucagon analogue. Class B G-protein-coupled receptors (GPCRs), which consist of an extracellular domain (ECD) and a transmembrane domain (TMD), respond to secretin peptides to play a key part in hormonal homeostasis, and are important therapeutic targets for a variety of diseases1,2,3,4,5,6,7,8. Previous work9,10,11 has suggested that peptide ligands bind to class B GPCRs according to a two-domain binding model, in which the C-terminal region of the peptide targets the ECD and the N-terminal region of the peptide binds to the TMD binding pocket. Recently, three structures of class B GPCRs in complex with peptide ligands have been solved12,13,14. These structures provide essential insights into peptide ligand recognition by class B GPCRs. However, owing to resolution limitations, the specific molecular interactions for peptide binding to class B GPCRs remain ambiguous. Moreover, these previously solved structures have different ECD conformations relative to the TMD, which introduces questions regarding inter-domain conformational flexibility and the changes required for receptor activation. Here we report the 3.0 A-resolution crystal structure of the full-length human glucagon receptor (GCGR) in complex with a glucagon analogue and partial agonist, NNC1702. This structure provides molecular details of the interactions between GCGR and the peptide ligand. It reveals a marked change in the relative orientation between the ECD and TMD of GCGR compared to the previously solved structure of the inactive GCGR–NNC0640–mAb1 complex. Notably, the stalk region and the first extracellular loop undergo major conformational changes in secondary structure during peptide binding, forming key interactions with the peptide. We further propose a dual-binding-site trigger model for GCGR activation—which requires conformational changes of the stalk, first extracellular loop and TMD—that extends our understanding of the previously established two-domain peptide-binding model of class B GPCRs.

The glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR) are members of the secretin-like class B family of G-protein-coupled receptors (GPCRs) and have opposing physiological roles in insulin release and glucose homeostasis. The treatment of type 2 diabetes requires positive modulation of GLP-1R to inhibit glucagon secretion and stimulate insulin secretion in a glucose-dependent manner. Here we report crystal structures of the human GLP-1R transmembrane domain in complex with two different negative allosteric modulators, PF-06372222 and NNC0640, at 2.7 and 3.0 Å resolution, respectively. The structures reveal a common binding pocket for negative allosteric modulators, present in both GLP-1R and GCGR and located outside helices V-VII near the intracellular half of the receptor. The receptor is in an inactive conformation with compounds that restrict movement of the intracellular tip of helix VI, a movement that is generally associated with activation mechanisms in class A GPCRs. Molecular modelling and mutagenesis studies indicate that agonist positive allosteric modulators target the same general region, but in a distinct sub-pocket at the interface between helices V and VI, which may facilitate the formation of an intracellular binding site that enhances G-protein coupling.

The representation of women in corporate directorships in Denmark has only been improving slowly over the last few years. Despite the slow progress at home and more active policies in neighboring countries and at the EU level, the Danish government has thus far resisted implementing board gender quotas. This chapter reviews the rules, trends and main debates surrounding board gender diversity in Denmark. We describe the main features of the country’s corporate governance system and overview the gender composition of Danish boards and the country’s efforts with regard to women’s representation in the top positions. We suggest that the low incidence of Danish women on boards is due to both the shortage of female candidates, especially women with leadership skills, as well as the persisting preferences of firms for “traditional” types of director characteristics and skills. We argue that further efforts in Denmark need to be directed toward facilitating women’s promotion to leadership positions, and also toward increasing firms’ (owners’) awareness of the benefits of gender-diverse boards.

In its decision in Vale, the Court of Justice takes another step forward, while still respecting its two-pronged case law on the nationality of companies. Analysing this case law shows a considerable move towards a genuine freedom of establishment for companies and paints a more nuanced picture than is normally acknowledged. However, the necessary legal certainty so paramount for business in these matters still requires actual legislation. In this respect, the question of establishment and the freedom of companies to choose their nationality remain unfinished business.