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Three-dimensional representations of G protein-coupled receptor structures and mechanisms

Publisher Summary G protein-coupled receptors (GPCRs) have been grouped into five somewhat distinct families: one resembling rhodopsin, another identified with the secretin receptor, a class related to the metabotropic glutamate receptor, another to the fungal pheromone receptor, and a class of CAMP receptors. The recent breakthrough in determining the crystal structure of rhodopsin has confirmed the general expectation that GPCRs are composed of seven helical transmembrane segments connected by intracellular and extracellular loop segments, as well as the expected topology of an extracellular N terminus and an intracellular C terminus. This chapter describes the construction, evaluation, and use of the three-dimensional (3D) molecular models of GPCRs from the various families reflects the general current understanding of their architecture. This understanding is implemented in the 3D receptor models based on a variety of direct experimental data, as well as results from various approaches from computational genomics, biophysics, and bioinformatics.

Functional Mechanisms of G Protein-Coupled Receptors in a Structural Context

The central role of G protein-coupled receptors (GPCRs) in most aspects of biological signal transduction has made them the object of extensive studies for a long period of time. These studies have revealed the key physiological roles of the many members of this family, and the manifold functions they have in the central nervous system (CNS) and the periphery (for recent reviews, see refs. [1,2]). Despite the abundance of information available in the literature, however, many of the fundamental questions regarding the molecular and structural requirements for GPCR function remain unanswered. A large number of reviews and compendia of results have been devoted to such fundamental elements in the biological mechanisms of GPCR (3–9). For this reason, we review here only some of the key aspects of recent progress in the development and application of approaches aiming to elucidate functional mechanisms of GPCRs in a detailed structural context. A central aim of our own collaborative studies of GPCRs is to develop such a coherent structural context (e.g., see [5,10–15]) that can serve in the interpretation, as well as the integration into a mechanistic understanding, of the abundant data about these systems. For this reason, we focus here specifically on the following three aspects of recent developments in the field: (1) the management of the copious data accumulated from structure-function studies, including genomic information; (2) some novel insights about intramolecular mechanisms triggering the activation of GPCRs; and (3) the recently characterized oligomerization of the receptors. The concluding Perspective section points to the integration of the mechanistic insights at the level of GPCR function with the growing understanding of signal-transduction pathways in the cells.