Principles of agonism: undressing efficacy.

Abstract

As the temperature and humidity rose in the auditorium during the heat-wave of the Italian alps, it became evident that, in fact, more was revealed of the bodies of certain distinguished pharmacologists than of the true nature of Stephenson's efficacy.Nevertheless, real 3D structures of receptors in their empty, apo-, form as well as in their holo-forms, i.e. in complex with different ligands: agonists, partial agonists, antagonists, etc. are currently becoming available, at least in the nuclear receptor field (Fig. 2Fig. 2). Thus, we are rapidly approaching a long-awaited point in time where pharmacologists and medicinal chemists can relate theoretical pharmacological concepts directly to 3D structures. This could soon be the case even for 7TM receptors. On the day of the meeting the structural basis for activation of the G protein, Ras, by the nucleotide exchange factor, Sos, was published[10xBorlack-Sjodin, P.A., Margerit, S.M., Bar-Sagi, D., and Kuriyan, J. Nature. 1998; 394: 337–343Crossref | PubMed | Scopus (430)See all References[10]. The `loosening' of the GDP (corresponding to efficacy—see above) was clearly shown to be achieved through two antiparallel helices extending from the Sos molecule and interacting with a switch domain on the G protein. It could be relevant that the main G protein-interacting domain of 7TM receptors also is represented by two antiparallel helices, i.e. the intracellular extensions of TM5 and TM6 (Ref. [11xAltenbach, C. et al. Biochemistry. 1995; 35: 12470–12478Crossref | Scopus (263)See all References[11]; Fig. 1Fig. 1).