G protein-coupled receptors (GPCRs) are a family of 7 pass transmembrane receptor proteins which have extremely important roles in signal transduction in response to a huge variety of stimuli (figure 1). Hormones, neurotransmitters, and ligands responsible for sight and taste, are just some of the many agonists that GPCR's respond to, accounting for an extremely large portion of the signalling pathways that occur. It is therefore no wonder that GPCR's have become the centre of so many relatively recent structural studies. Countless x-ray crystallography studies have been carried out on GPCR's in recent years, especially on the inactive state of rhodopsin ( one of the many GPCR's). Rhodopsin proved great for crystallisation due to its stability. The success of discovering Rhodopsin's structure via X-ray crystallography lead to exciting new studies on another, now key model, of GPCR; the β2 adrenergic receptor (β2 AR) a neurotransmitter receptor, activated on binding adrenaline, that causes sympathetic responses. The experimental procedure that lead to obtaining the x-ray crystal structure of the β2 adrenergic receptor and discussions about its structure is the main topic of this Blog. We hope you enjoy reading it!
The huge boom of relatively recent studies involving GPCR's have allowed us to discover various components of GPCR signalling and have given us an insight into the structural basis behind their signalling function. Even so there was still confusion as to whether the heterotrimeric GTP binding protein (G protein) was a part of the GPCR as a complex or a separate molecule all together. This lead to the investigation, discussed on this blog, into the structure of the β2 AR-Gs protein complex and the subsequent construction of its ternary structure from diffraction data. Various other techniques, such as electron microscopy analysis, were used in conjunction with x-ray crystallography in order to overcome some problems encountered in the past arising from the structural flexibility and instability of GPCR's. The hope was to finally elucidate how the two components, GPCR and G-protein, interact. All this is discussed in the blog, click on the top tabs to find out more! (Rasmussen, S. G. F. et al., 2011)
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| Figure1. Activation of the 7 transmembrane GPCR leading to subsequent activation of Adenylyl cyclase. 1. Inactive unbound GPCR coupled to an inactive G-protein with GDP bound to its alpha-subunit. 2. Agonist binds GPCR, activating it which induces conformational changes subsequently activating the G-protein. This leads to GDP-GTP exchange on the alpha-subunit of the G-protein. 3. G-protein subunits dissociate and the GTP-bound alpha-subunit activates Adenylyl cyclase to produce cAMP from ATP. |
Reference:
Rasmussen SG, DeVree BT, Zou Y, Kruse AC, Chung KY, Kobilka TS, Thian FS, Chae PS, Pardon E, Calinski D, Mathiesen JM, Shah ST, Lyons JA, Caffrey M, Gellman SH, Steyaert J, Skiniotis G, Weis WI, Sunahara RK, Kobilka BK.
