| Attributs | Valeurs |
|---|
| type
| |
| Is Part Of
| |
| Subject
| |
| Title
| - Crystal Structure of 6α-(Hydroxymethyl)penicillanateComplexed to the TEM-1 β-Lactamase from Escherichia coli: Evidence on the Mechanism of Action of a Novel InhibitorDesigned by a Computer-Aided Process
|
| has manifestation of work
| |
| related by
| |
| Author
| |
| Abstract
| - The crystal structure of the complex of the TEM-1 β-lactamasefrom Escherichia coli inhibited by 6α-(hydroxymethyl)penicillanic acid (1) is reported herein.This is the first structure for an acyl-enzymeintermediatewith a substrate reported for a native class A β-lactamase. Thiscompound was designed and synthesized as amolecule that would acylate the active site of the enzyme, but wouldresist deacylation by virtue of the fact that itsC6α hydroxymethyl moiety was expected tooccupy the space near the hydrolytic water molecule (J. Am. Chem.Soc.1995, 117, 11055). The crystal structure ofthe acyl-enzyme species is closely similar to one of the twoenergy-minimized acyl-enzyme models generated in the course of the designaspect of the work. The crystal structureprovides evidence for a number of mechanistic features for theinhibition process and the ultimate recovery of theactivity. Our results reported herein are consistent with theside-chain carboxylate of Glu-166 being the active-sitebasic function that activates the hydrolytic water for the deacylationstep in the course of catalysis by class Aβ-lactamases. The design principles applied for compound1 hold the promise of general utility for developmentofnovel inhibitors for other hydrolytic enzymes.
|
| article type
| |
| is part of this journal
| |
