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- W2969571807 abstract "A pre-existing, allosteric equilibrium between closed (E*) and open (E) conformations of the active site influences the level of activity in the trypsin fold and defines ligand binding according to the mechanism of conformational selection. Using the clotting protease thrombin as a model system, we investigate the molecular determinants of the E*-E equilibrium through rapid kinetics and X-ray structural biology. The equilibrium is controlled by three residues positioned around the active site. W215 on the 215-217 segment defining the west wall of the active site controls the rate of transition from E to E* through hydrophobic interaction with F227. E192 on the opposite 190-193 segment defining the east wall of the active site controls the rate of transition from E* to E through electrostatic repulsion of E217. The side chain of E217 acts as a lever that moves the entire 215-217 segment in the E*-E equilibrium. Removal of this side chain converts binding to the active site to a simple lock-and-key mechanism and freezes the conformation in a state intermediate between E* and E. These findings reveal a simple framework to understand the molecular basis of a key allosteric property of the trypsin fold." @default.
- W2969571807 created "2019-08-29" @default.
- W2969571807 creator A5013803228 @default.
- W2969571807 creator A5046701540 @default.
- W2969571807 creator A5059884782 @default.
- W2969571807 creator A5073341567 @default.
- W2969571807 creator A5077357809 @default.
- W2969571807 date "2019-08-23" @default.
- W2969571807 modified "2023-10-18" @default.
- W2969571807 title "Residues W215, E217 and E192 control the allosteric E*-E equilibrium of thrombin" @default.
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- W2969571807 doi "https://doi.org/10.1038/s41598-019-48839-1" @default.