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Open Access Editorial [Hot Topic: Recent Achievements on G-Protein Coupled Receptors (Guest Editor: Slawomir Filipek)]

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Two important breakthroughs, in crystallography and in molecular simulations, moved forward investigations of the G-protein coupled receptors (GPCRs). Based on the recent crystal structures of GPCRs with agonists, and also on the results from very long simulations exceeding the microsecond frontier, it was possible to answer the fundamental questions about their multiple activation schemes in anticipation of a more effective drug design. The aim of this Hot Topic is to show the recent advancements in understanding the structure and, especially, the function of these highly elusive receptors. Recent studies of GPCRs changed the old dogma of a simple classification of the receptor ligands into agonists, antagonists and inverse agonists. Now, it is apparent that the same ligand can play diverse roles even in the same receptor acting as an agonist or an antagonist in different signaling pathways. Therefore, not a bare receptor but rather a receptor-ligand pair emerges as the smallest signaling unit. The scope of the reviews embraces recent achievements in the GPCR area which attempt to unravel the following pieces of the multithread puzzle of GPCRs: (1) The molecular evolution of the most populated class-A of GPCRs and possible causes of diversification of this huge family; (2) Structures of β-adrenergic receptors with agonists and antagonists including the structure of a newly crystallized β2AR-Gαβγ protein complex. β-Adrenergic receptors and the rhodopsin/opsin system are the bestcharacterized GPCRs also in terms of the activation schemes; (3) The ensemble of the GPCR active states and their contribution to the diversity of their signaling. Any changes in this signaling behavior have serious implications in health and disease; (4) The crosstalk between receptors in heteromers which can modulate signaling effects. Such physical interaction between receptors is known to exist but its functional implications are still elusive; (5) The action of molecular switches in GPCRs which perform the job of receptor activation; and (6) A description of results from very long time scale simulations which were subsequently validated by experiments. GPCRs are still mysterious in their activation scheme and multiple signaling but we are getting closer to better understanding of their secrets.

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Document Type: Research Article

Publication date: 2012-03-01

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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