Nobel de química 2012: receptores acoplados à proteína G
Journal of the Brazilian Chemical Society
for their studies on the G-proteincoupled receptors (GPCRs). Lefkowitz and Kobilka's discoveries led to the elucidation of how cells communicate with each other and perceive stimuli from the environment. GPCRs are proteins embedded in the biological membranes and help to transmit external signals to the interior of cells, acting in the regulation of several physiological functions, ranging from the detection of physical sensations (e.g. light) to the hormonal regulation. GPCRs play a central
... e in cellular and biochemical processes, acting as molecular targets for many drugs, including muscarinic, adrenergic, dopaminergic, serotonergic, opiate and purinergic, among other receptors. About 50% of all available drugs in the therapeutics bind to any of the various subtypes of GPCRs. Important examples include the anti-ulcer ranitidine (Zantac) ® , the H 2 histaminic receptor antagonist; the antipsychotic olanzapine (Zyprexa) ® , the 5-HT 2 serotonergic receptor antagonist and the anti-allergic desloratadine (Desalex) ® , the H 1 histaminic receptor antagonist. Several important advances have been recorded since the discovery of GPCRs, with emphasis on the elucidation of the 3D structures of different subtypes and their complexes, by means of experimental methods such as X-ray crystallography. Such structural knowledge has enabled a better understanding of the biochemical mechanisms of this class of receptors and the establishment of the molecular bases that have led to the discovery of new drugs. GPCRs have a similar conserved 3D folding of the polypeptide chain, comprising an N-terminal extracellular domain, seven transmembrane helices and an intracellular C-terminal domain. GPCRs interact with proteins located on the inner cell membrane. These specific proteins, known as G-proteins, are heterotrimers consisting of α, β and γ subunits. In 1980, Lefkowitz and collaborators proposed an activation mechanism involving the formation of a ternary complex of the extracellular ligand (agonist), the transmembrane GPCR and the intracellular G-protein acting as a signal activator.