Also known as seven transmembrane (heptahelical) receptors, due to their characteristic membrane topology (seven transmembrane helices, extracellular N-terminus and intracellular C-terminus). They are transmembrane proteins acting as the sensory component of cellular signalling pathways. GPCRs, are a key class of eukaryotic membrane receptors and roughly 50% of all small molecule therapeutics target GPCRs. Vision, smell and some of taste uses GPCRs. Ligands for GPCRs cover a wide range of organic chemical space, including proteins, peptides, sugars, amines and amino-acids, nucleotides, lipids and more. They transduce signals from extracellular space into the cell, through their interaction with G proteins, which act as switches forming hetero-trimers composed of different subunits (a,ß,?). Two GPCRs’ crystal structures are currently available, the structure of Rhodopsin and the recently solved three-dimensional structure of beta-2 Adrenergic Receptor.
Published in Chapter:
Computational Methods for the Prediction of GPCRs Coupling Selectivity
Nikolaos G. Sgourakis (Rensselaer Polytechnic Institute, USA), Pantelis G. Bagos (University of Central Greece, and University of Athens, Greece), and Stavros J. Hamodrakas (University of Athens, Greece)
Copyright: © 2009
|Pages: 15
DOI: 10.4018/978-1-60566-076-9.ch009
Abstract
GPCRs comprise a wide and diverse class of eukaryotic transmembrane proteins with well-established pharmacological significance. As a consequence of recent genome projects, there is a wealth of information at the sequence level that lacks any functional annotation. These receptors, often quoted as orphan GPCRs, could potentially lead to novel drug targets. However, typical experiments that aim at elucidating their function are hampered by the lack of knowledge on their selective coupling partners at the interior of the cell, the G-proteins. Up-to-date, computational efforts to predict properties of GPCRs have been focused mainly on the ligand-binding specificity, while the aspect of coupling has been less studied. Here, we present the main motivations, drawbacks, and results from the application of bioinformatics techniques to predict the coupling specificity of GPCRs to G-proteins, and discuss the application of the most successful methods in both experimental works that focus on a single receptor and large-scale genome annotation studies.