(320d) Evolution-Guided Design of Phosphatase Inhibitors

The design of inhibitors that bind tightly and selectively to proteins represents a longstanding challenge of applied biophysics. In this talk, we use a broad set of biophysical analyses of protein tyrosine phosphatase 1B (PTP1B), an important regulator of cell signaling and an elusive drug target, to show how natural evolutionary constraints on the structures of biomolecules can guide efforts in inhibitor design. We begin by describing a plant-derived metabolite that can inhibit PTP1B by binding to its active site in a manner that stabilizes the enzyme in an inactive conformation, and we show that evolutionarily accessible changes in the structure of this metabolite can significantly improve its potency. Using a multi-dimensional evolutionary analysis, in turn, we provide evidence that PTP1B possesses an allosteric network that is broadly conserved across the PTP family, and we show that this network is functionally intact (i.e., susceptible to inhibitor-mediated modulation) in a set of sequence-diverse PTPs. The metabolites and allosteric sites identified in this study provide new starting points for building inhibitors of PTPs—a class of enzymes that has long eluded drug design. More broadly, our findings support the notion that the evolutionary trajectories of secondary metabolites enable an efficient sampling of molecular structures likely to bind proteins, and they provide rigorous evidence that patterns of residue-residue coevolution within protein families can reveal sets of functionally conserved, yet structurally distinct allosteric sites.