Competition in drug binding and … the race to equilibrium.

Binding kinetics has become a popular topic in pharmacology due to its potential contribution to the selectivity and duration of drug action. Yet, the overall kinetic aspects of complex binding mechanisms are still merely described in terms of elaborate algebraic equations. Interestingly, it has been recommended some 10 years ago to examine such mechanisms in terms of binding fluxes instead of the conventional rate constants.

Distinct In Vitro Binding Profile of the Somatostatin Receptor Subtype 2 Antagonist [Lu]Lu-OPS201 Compared to the Agonist [Lu]Lu-DOTA-TATE.

Treatment of neuroendocrine tumours with the radiolabelled somatostatin receptor subtype 2 (SST) peptide agonist [Lu]Lu-DOTA-TATE is effective and well-established. Recent studies suggest improved therapeutic efficacy using the SST peptide antagonist [Lu]Lu-OPS201. However, little is known about the cellular mechanisms that lead to the observed differences.

Induced fit versus conformational selection: From rate constants to fluxes… and back to rate constants.

Induced fit- (IF) and conformational selection (CS) binding mechanisms have long been regarded to be mutually exclusive. Yet, they are now increasingly considered to produce the final ligand-target complex alongside within a thermodynamic cycle. This viewpoint benefited from the introduction of binding fluxes as a tool for analyzing the overall behavior of such cycle.

Fluxes for Unraveling Complex Binding Mechanisms.

A decade ago, many high-affinity drugs were thought to bind to their target via an induced-fit pathway instead of conformational selection. Yet, both pathways make up part of a thermodynamic cycle, and, owing to binding flux-based approaches, it is now rather considered that they act in parallel and also that their relative contribution to the final ligand-target complex depends on the ligand concentration. Those approaches are of increasing interest, but published data still merely refer to the peculiar situation of equilibrium binding.

Mechanisms of PDZ domain scaffold assembly illuminated by use of supported cell membrane sheets.

PDZ domain scaffold proteins are molecular modules orchestrating cellular signalling in space and time. Here, we investigate assembly of PDZ scaffolds using supported cell membrane sheets, a unique experimental setup enabling direct access to the intracellular face of the cell membrane. Our data demonstrate how multivalent protein-protein and protein-lipid interactions provide critical avidity for the strong binding between the PDZ domain scaffold proteins, PICK1 and PSD-95, and their cognate transmembrane binding partners.