Allostery: an illustrated definition for the ‘second secret of life’

Abstract

Although allosteric regulation is the 'second secret of life', the molecular mechanisms that give rise to allostery currently elude understanding. In my opinion, experimental progress is hampered by a commonly used but misleading definition of allostery as protein structural changes that are elicited by the binding of a single ligand. Allostery is more strictly defined in functional terms as a comparison of how one ligand binds in the absence, versus the presence, of a second ligand. Therefore, as each of the two binding events involves two protein complexes, a study of allostery must consider four complexes and not just two. Such a comparison can distinguish allosteric from non-allosteric protein changes, the importance of which is frequently overlooked. When a study of all four complexes is not feasible, an alternative, albeit limited, strategy can identify subsets of allosteric-specific changes.

Hill coefficients, dose–response curves and allosteric mechanisms

“…A different type of allosteric interactions, namely those between substrate and other ("allosteric") protein binding sites, had been identified in crystal structures of known inhibitors [8]. This eventually led to a much broader definition of allostery [9,10], where allosteric interactions are seen as conformational changes of a protein elicited by one compound, which then affect the binding of or the functional response to another compound. This definition is semantically correct [10], but it is not surprising [11], and indeed an intrinsic property of proteins [12], that a ligand that binds one site should affect its conformation elsewhere.…”

Structural basis for the catalytic mechanism and α-ketoglutarate cooperativity of glutamate dehydrogenase

“…Obtaining quantitative molecular description of enzyme allostery has remained a central focus in biology (2). However, trapping the various structural intermediate states to gain detailed understanding about the kinetic properties of allosteric enzymes has remained very challenging (2,3). Glutamate dehydrogenase (GDH) is an oxidoreductase important for ammonia metabolism in archebacteria, eubacteria, and eukaryotes (4,5).…”

Mécanisme d’activation de l’oncogèneBRAF

“…Perspectives sur la signalisation modulée par allostérie La modification de l'activité d'une enzyme envers son substrat par la liaison d'une troisième molécule se nomme allostérie [8]. Les affinités du régula-teur lacR pour l'ADN ou de l'hémoglobine pour l'oxygène, respectivement modulées par le lactose et l'oxygène, sont des exemples classiques d'interactions modulées par allostérie [8].…”

“…Les affinités du régula-teur lacR pour l'ADN ou de l'hémoglobine pour l'oxygène, respectivement modulées par le lactose et l'oxygène, sont des exemples classiques d'interactions modulées par allostérie [8]. Traditionnellement, l'allostérie était principalement considérée dans l'étude d'enzymes du métabolisme cellulaire.…”