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Advances in the Development and Application of Computational Methodologies for Structural Modeling of G-Protein Coupled Receptors.

ABSTRACT: BACKGROUND: Despite the large amount of experimental data accumulated in the past decade on G-protein coupled receptor (GPCR) structure and function, understanding of the molecular mechanisms underlying GPCR signaling is still far from being complete, thus impairing the design of effective and selective pharmaceuticals. OBJECTIVE: Understanding of GPCR function has been challenged even further by more recent experimental evidence that several of these receptors are organized in the cell membrane as homo- or hetero-oligomers, and that they may exhibit unique pharmacological properties. Given the complexity of these new signaling systems, researcher's efforts are turning increasingly to molecular modeling, bioinformatics and computational simulations for mechanistic insights of GPCR functional plasticity. METHODS: We review here current advances in the development and application of computational approaches to improve prediction of GPCR structure and dynamics, thus enhancing current understanding of GPCR signaling. RESULTS/CONCLUSIONS: Models resulting from use of these computational approaches further supported by experiments are expected to help elucidate the complex allosterism that propagates through GPCR complexes, ultimately aiming at successful structure-based rational drug design.

SUBMITTER: Mobarec JC

PROVIDER: S-EPMC2723956 | biostudies-literature | 2008 Mar

REPOSITORIES: biostudies-literature

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Advances in the Development and Application of Computational Methodologies for Structural Modeling of G-Protein Coupled Receptors.

Mobarec Juan Carlos JC Filizola Marta M

Expert opinion on drug discovery 20080301 3

BACKGROUND: Despite the large amount of experimental data accumulated in the past decade on G-protein coupled receptor (GPCR) structure and function, understanding of the molecular mechanisms underlying GPCR signaling is still far from being complete, thus impairing the design of effective and selective pharmaceuticals. OBJECTIVE: Understanding of GPCR function has been challenged even further by more recent experimental evidence that several of these receptors are organized in the cell membrane ...[more]

PMID: 19672320

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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.

Dataset Information

Advances in the Development and Application of Computational Methodologies for Structural Modeling of G-Protein Coupled Receptors.

Publications

Advances in the Development and Application of Computational Methodologies for Structural Modeling of G-Protein Coupled Receptors.

Similar Datasets

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