Spotlight on ECI researchers
Institut de Génomique Fonctionnelle, Montpellier, France
Machine learning of sequence-function relationships of olfactory receptors
Queen’s University Belfast, Northern Ireland
Ligand binding site mapping at GPCR-Lipid Interface
Targeting G protein-coupled receptors (GPCRs) through allosteric sites offers advantages over orthosteric sites in identifying drugs with increased selectivity and potentially reduced side effects (1-4). We have recently developed a probe confined dynamic mapping protocol to map GPCRs allosteric sites at various locations (5). Here, we propose an improved protocol that allows efficient prediction of allosteric sites at the receptor-lipid interface. The P2Y1 purinergic and CB1 cannabinoid receptors were selected for protocol validation. We show that our protocol together with the sequence analysis is specific in identifying an allosteric site of a compound and works in various receptor conformations. The protocol provides a fast and efficient prediction of key polar interactions in an allosteric cavity at the lipid interface.
University of Ottawa, Canada
A positive allosteric modulator of M1 Acetylcholine receptors improves pathology and cognitive deficits in female APPswe/PSEN1ΔE9 mice
Institute of Experimental Medicine, Budapest, Hungary
PharmacoSTORM: a novel approach for the nanoscale imaging of drug binding sites
University of Arizona, USA
The Modulation of Conformational Energetics of GPCR Activation by Water
Prothoracicostatic Activity of the Ecdysis-Regulating Neuropeptide Crustacean Cardioactive Peptide (CCAP) in the Desert Locust
Accurate control of innate behaviors associated with developmental transitions requires functional integration of hormonal and neural signals. Insect molting is regulated by a set of neuropeptides, which trigger periodic pulses in ecdysteroid hormone titers and coordinate shedding of the old cuticle during ecdysis. In the current study, we demonstrate that crustacean cardioactive peptide (CCAP), a structurally conserved neuropeptide described to induce the ecdysis motor program, also exhibits a previously unknown prothoracicostatic activity to regulate ecdysteroid production in the desert locust, Schistocerca gregaria. We identified the locust genes encoding the CCAP precursor and three G protein-coupled receptors that are activated by CCAP with EC50 values in the (sub)nanomolar range. Spatiotemporal expression profiles of the receptors revealed expression in the prothoracic glands, the endocrine organs where ecdysteroidogenesis occurs. RNAi-mediated knockdown of CCAP precursor or receptors resulted in significantly elevated transcript levels of several Halloween genes, which encode ecdysteroid biosynthesis enzymes, and in elevated ecdysteroid levels one day prior to ecdysis. Moreover, prothoracic gland explants exhibited decreased secretion of ecdysteroids in the presence of CCAP. Our results unequivocally identify CCAP as the first prothoracicostatic peptide discovered in a hemimetabolan species and reveal the existence of an intricate interplay between CCAP signaling and ecdysteroidogenesis.
Evolutionary history of histamine receptors: Early vertebrate origin and expansion of the H3 - H4 subtypes