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Chemokine receptors and other G protein-coupled receptors.

ABSTRACT: Class A G protein-coupled receptors (GPCRs), including the chemokine receptors, CCR5 and CXCR4, share a seven transmembrane-spanning alpha-helix architecture that accommodates signal propagation from across biological membranes. CXCR4 and CCR5 are utilized as co-receptors during HIV viral entry and, therefore, crystal structures of GPCRs aid in the understanding of their function in viral entry.Recent progress in structure determination of class A GPCRs, which include vertebrate and invertebrate rhodopsin as well as adrenergic and adenosine receptors, provides molecular templates for how this diverse group of transmembrane receptors functions. Each of these GPCRs differs in how specific ligands bind to the transmembrane core, underscoring that additional structures of GPCRs from other subfamilies are needed to facilitate rational drug design. More recent studies also indicate a need to consider the more complex character of GPCRs, such as their oligomerization and dynamics.Recently, the atomic structures of invertebrate rhodopsin, beta1-adrenergic and beta2-adrenergic receptors and the A(2A)-adenosine receptor have been solved via X-ray crystallography. The impact that these structures have on the biochemistry of viral entry and signal transduction is discussed. Because the chemokine receptors have proven refractory to structural studies thus far, further structural study of the chemokine receptors will be essential to understanding ligand binding, activation and function as co-receptors during viral entry.

SUBMITTER: Lodowski DT

PROVIDER: S-EPMC2771364 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Chemokine receptors and other G protein-coupled receptors.

Lodowski David T DT Palczewski Krzysztof K

Current opinion in HIV and AIDS 20090301 2

<h4>Purpose of review</h4>Class A G protein-coupled receptors (GPCRs), including the chemokine receptors, CCR5 and CXCR4, share a seven transmembrane-spanning alpha-helix architecture that accommodates signal propagation from across biological membranes. CXCR4 and CCR5 are utilized as co-receptors during HIV viral entry and, therefore, crystal structures of GPCRs aid in the understanding of their function in viral entry.<h4>Recent findings</h4>Recent progress in structure determination of class ...[more]

PMID: 19339946

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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 β(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 α-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

Chemokine receptors and other G protein-coupled receptors.

Publications

Chemokine receptors and other G protein-coupled receptors.

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