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Recent advances in computational studies of GPCR-G protein interactions.

ABSTRACT: Protein-protein interactions are key in cellular signaling. G protein-coupled receptors (GPCRs), the largest superfamily of human membrane proteins, are able to transduce extracellular signals (e.g., hormones and neurotransmitters) to intracellular proteins, in particular the G proteins. Since GPCRs serve as primary targets of ~1/3 of currently marketed drugs, it is important to understand mechanisms of GPCR signaling in order to design selective and potent drug molecules. This chapter focuses on recent advances in computational studies of the GPCR-G protein interactions using bioinformatics, protein-protein docking and molecular dynamics simulation approaches.

SUBMITTER: Wang J

PROVIDER: S-EPMC6986689 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Recent advances in computational studies of GPCR-G protein interactions.

Wang Jinan J Miao Yinglong Y

Advances in protein chemistry and structural biology 20190103

Protein-protein interactions are key in cellular signaling. G protein-coupled receptors (GPCRs), the largest superfamily of human membrane proteins, are able to transduce extracellular signals (e.g., hormones and neurotransmitters) to intracellular proteins, in particular the G proteins. Since GPCRs serve as primary targets of ~1/3 of currently marketed drugs, it is important to understand mechanisms of GPCR signaling in order to design selective and potent drug molecules. This chapter focuses o ...[more]

PMID: 31036298

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Project description:BackgroundBabesia spp. are protozoan parasites of great medical and veterinary importance, especially in the northern Hemisphere. Ticks are known vectors of Babesia spp., although some Babesia-tick interactions have not been fully elucidated.MethodsThe present review was performed to investigate the specificity of Babesia-tick species interactions that have been identified using molecular techniques in studies conducted in the last 20 years under field conditions. We aimed to indicate the main vectors of important Babesia species based on published research papers (n = 129) and molecular data derived from the GenBank database.ResultsRepeated observations of certain Babesia species in specific species and genera of ticks in numerous independent studies, carried out in different areas and years, have been considered epidemiological evidence of established Babesia-tick interactions. The best studied species of ticks are Ixodes ricinus, Dermacentor reticulatus and Ixodes scapularis (103 reports, i.e. 80% of total reports). Eco-epidemiological studies have confirmed a specific relationship between Babesia microti and Ixodes ricinus, Ixodes persulcatus, and Ixodes scapularis and also between Babesia canis and D. reticulatus. Additionally, four Babesia species (and one genotype), which have different deer species as reservoir hosts, displayed specificity to the I. ricinus complex. Eco-epidemiological studies do not support interactions between a high number of Babesia spp. and I. ricinus or D. reticulatus. Interestingly, pioneering studies on other species and genera of ticks have revealed the existence of likely new Babesia species, which need more scientific attention. Finally, we discuss the detection of Babesia spp. in feeding ticks and critically evaluate the data on the role of the latter as vectors.ConclusionsEpidemiological data have confirmed the specificity of certain Babesia-tick vector interactions. The massive amount of data that has been thus far collected for the most common tick species needs to be complemented by more intensive studies on Babesia infections in underrepresented tick species.

Project description:The years 2000 and 2007 witnessed milestones in current understanding of G protein-coupled receptor (GPCR) structural biology. In 2000 the first GPCR, bovine rhodopsin, was crystallized and the structure was solved, while in 2007 the structure of ?(2)-adrenergic receptor, the first GPCR with diffusible ligands, was determined owing to advances in microcrystallization and an insertion of the fast-folding lysozyme into the receptor. In parallel with those crystallographic studies, the biological and biochemical characterization of GPCRs has advanced considerably because those receptors are molecular targets for many of currently used drugs. Therefore, the mechanisms of activation and signal transduction to the cell interior deduced from known GPCRs structures are of the highest importance for drug discovery. These proteins are the most diversified membrane receptors encoded by hundreds of genes in our genome. They participate in processes responsible for vision, smell, taste and neuronal transmission in response to photons or binding of ions, hormones, peptides, chemokines and other factors. Although the GPCRs share a common seven-transmembrane ?-helical bundle structure their binding sites can accommodate thousands of different ligands. The ligands, including agonists, antagonists or inverse agonists change the structure of the receptor. With bound agonists they can form a complex with a suitable G protein, be phosphorylated by kinases or bind arrestin. The discovered signaling cascades invoked by arrestin independently of G proteins makes the GPCR activating scheme more complex such that a ligand acting as an antagonist for G protein signaling can also act as an agonist in arrestin-dependent signaling. Additionally, the existence of multiple ligand-dependent partial activation states as well as dimerization of GPCRs result in a 'microprocessor-like' action of these receptors rather than an 'on-off' switch as was commonly believed only a decade ago.

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Recent advances in computational studies of GPCR-G protein interactions.

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Recent advances in computational studies of GPCR-G protein interactions.

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