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18 The Molecular Mechanism of trp Repression

Paul B. Sigler


Transcription of the trp biosynthetic operons in enteric bacteria is controlled mainly by an allosterically regulated repressor. High-resolution crystallography combined with genetics, in vitro mutagenesis, and physico-biochemical methods have defined the molecular mechanism in detailed chemical terms. The inactive trp aporepressor is converted to the active repressor by binding the corepressor, L-tryptophan. The chain of stereochemical events that underlies this transition have been identified. For the repressor to form an operator-specific binding surface, the corepressor must bind with severe torsional strain. This is achieved by strong, specific binding sites for indole and α-amino moieties, thereby ensuring that L-tryptophan will be the only amino acid or indole derivative that will serve as a corepressor. Operator binding employs stereo-specific, water-mediated hydrogen bonds between the protein’s recognition surface and the identity elements of the DNA. These water molecules are firmly fixed to the protein even in the absence of DNA. Significant deformation of the DNA contributes to the creation of the specific protein-DNA interface. This deformability may be sequence-dependent; if so, this would imply an “indirect readout” of the operator sequence.

In this paper, I describe the detailed molecular mechanism of the trp repressor/operator system. Special interest in this system stems from several sources. First, it is an example of an allosterically modulated transcriptional regulator; that is, the protein’s function is regulated by a small effector molecule working through a simple negative feedback

As with most synthetic systems, the regulatory ligand is the end product of the regulated pathway. Here the...

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