The design of inhibitors that bind tightly and selectively to proteins represents a longstanding challenge of applied biophysics. This study uses a broad set of experimental and computational 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. Results suggest that abietic acid, a plant-derived secondary metabolite, can inhibit PTP1B by stabilizing its catalytically essential WPD loop in an inactive conformation, and they show that minor, evolutionarily accessible changes in the structures of abietane-type diterpenoids can significantly improve potency. A multidisciplinary evolutionary analysis, in turn, indicates that protein tyrosine phosphatases share a conserved allosteric network that makes them susceptible to inhibitors that bind to poorly conserved regions. The diterpenoids 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. The central 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.<br/>

Evolution-guided design of phosphatase inhibitors

2019 Spring National Meeting

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