Soft agonist receptor interactions: Theoretical and experimental simulation of the active site of the receptor of sweet molecules

Abstract

The structure-activity relationship of sweet molecules is chosen as an example to illustrate a mechanistic approach of soft agonist-receptor interactions. It is shown that an essentially geometric model of the receptor site can explain the activity of most sweet molecules, both rigid and flexible. The relevant conformations of flexible molecules in solution are extracted from a combination of N M R data and of energy calculations. A possible experimental simulation of the receptor environment in solution is illustrated by the complex of a dipeptide sweetener with a crown-ether.

The history of sweet taste: not exactly a piece of cake

“…Over a period of ca. 40 years, from the 60s to 2001, these studies led to the development of different models of the receptor active site (Shallenberger and Acree, 1967;Kier, 1972;Temussi et al, 1978Temussi et al, , 1984Temussi et al, , 1991Iwamura, 1981;Goodman et al, 1987;Tinti and Nofre, 1991).…”

“…These studies, elaborated even further by Oertly and Myers (1919), tried to attribute this ability to ordinary chemical groups such as OH, carboxyl or amino moieties, called 'glucophores', and the ability to increase the potency to other groups, called 'auxogluc', but it was soon clear that these groups belonged to sweet and tasteless molecules with similar frequency (Moncrieff, 1967). The interest was soon redirected towards the development of more general models of the receptor active site derived from the shape of conformationally rigid sweet molecules, used as molecular molds (Shallenberger and Acree, 1967;Kier, 1972;Temussi et al, 1978Temussi et al, , 1984Temussi et al, , 1991Kamphuis et al, 1992;Iwamura, 1981;Goodman et al, 1987).…”

Structural determination of the active site of a sweet protein A 1H NMR investigation of pMNEI

“…These circumstances have stimulated the development of general models of the receptor active site [2][3][4][5][6][7][8][9][10][11][12].…”

Interaction of sweet proteins with their receptor

“…The great majority of sweet molecules are small molecular mass compounds [3] but a few sweet proteins have also been identified [4]. Low molecular mass sweet compounds and sweet proteins interact with the same receptor, the human T1R2-T1R3 receptor [5]; accordingly, it seems natural to look for a similar mechanism when trying to explain the taste of these proteins.Early models of the active site of the sweet receptor, proposed before the nature of the receptor was elucidated, were derived from the shape of conformationally rigid sweeteners, used as molecular molds [6][7][8][9][10][11][12]. Different models differ in details of the shape of the active site but there is a consensus on the presence, in the sweetener, of two groups involved in hydrogen bonding with the receptor, the so-called AH-B entity [6], and of an apolar group at a precise distance with respect to the AH-B entity [7].…”

“…Different models differ in details of the shape of the active site but there is a consensus on the presence, in the sweetener, of two groups involved in hydrogen bonding with the receptor, the so-called AH-B entity [6], and of an apolar group at a precise distance with respect to the AH-B entity [7]. A well known exemplification of these three groups is provided by the carboxyl (AH) and amino (B) groups of Asp and the aromatic ring of Phe in aspartame [9]. Although designed for small molecules, these models could be compatible also with the interaction of macromolecular sweeteners with the receptor, provided sweet macromolecules possess a 'sweet finger' that can probe the active site.…”