Mechanism of allosteric activation of an enzyme by an inhibitor

The finding that an inhibitor activates an enzyme appears counterintuitive. How can an inhibitor, which binds to the active site, increase the enzyme’s activity? In this study, researchers at IBS (NMR, MICA and PG groups), in collaboration with colleagues in Nancy and Zaragoza, revealed how the 300 kDa large protease ClpP undergoes this intriguing allosteric activation by an inhibitor as well as by substrates. A multi-technique approach, involving X-ray crystallography, solution- and solid-state NMR, molecular dynamics simulations and calorimetry, shows that substoichiometric binding of inhibitors to active sites shifts the equilibrium in this oligomeric protein to a more active extended state. The findings may provide new routes for the development of drugs of this potential antibiotic protein target.

Mechanism of the allosteric activation of the ClpP protease machinery by substrates and active-site inhibitors. Felix J, Weinhäupl K, Chipot C, Dehez F, Hessel A, Gauto DF, Morlot C, Abian O, Gutsche I, Velazquez-Campoy A, Schanda P, Fraga H. Science Advances; Vol. 5, no. 9, eaaw3818