GPCRs (G-protein-coupled receptors) are seven-transmembrane helix proteins that transduce exogenous and endogenous signals to modulate the activity of downstream effectors inside the cell. Despite the relevance of these proteins in human physiology and pharmaceutical research, we only recently started to understand the structural basis of their activation mechanism. In the period 2008–2011, nine active-like structures of GPCRs were solved. Among them, we have determined the structure of light-activated rhodopsin with all the features of the active metarhodopsin-II, which represents so far the most native-like model of an active GPCR. This structure, together with the structures of other inactive, intermediate and active states of rhodopsin constitutes a unique structural framework on which to understand the conserved aspects of the activation mechanism of GPCRs. This mechanism can be summarized as follows: retinal isomerization triggers a series of local structural changes in the binding site that are amplified into three intramolecular activation pathways through TM (transmembrane helix) 5/TM3, TM6 and TM7/TM2. Sequence analysis strongly suggests that these pathways are conserved in other GPCRs. Differential activation of these pathways by ligands could be translated into the stabilization of different active states of the receptor with specific signalling properties.
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Conference Article|
March 21 2012
Conserved activation pathways in G-protein-coupled receptors
Xavier Deupi;
Xavier Deupi
*Condensed Matter Theory Group, Paul Scherrer Institut, Villigen PSI, Switzerland
†Laboratory of Biomolecular Research, Paul Scherrer Institut, Villigen PSI, Switzerland
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Jörg Standfuss;
Jörg Standfuss
†Laboratory of Biomolecular Research, Paul Scherrer Institut, Villigen PSI, Switzerland
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Gebhard Schertler
Gebhard Schertler
1
†Laboratory of Biomolecular Research, Paul Scherrer Institut, Villigen PSI, Switzerland
1To whom correspondence should be addressed (emailgebhard.schertler@psi.ch).
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Publisher: Portland Press Ltd
Received:
January 06 2012
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem Soc Trans (2012) 40 (2): 383–388.
Article history
Received:
January 06 2012
Citation
Xavier Deupi, Jörg Standfuss, Gebhard Schertler; Conserved activation pathways in G-protein-coupled receptors. Biochem Soc Trans 1 April 2012; 40 (2): 383–388. doi: https://doi.org/10.1042/BST20120001
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