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Summary

Genome analysis has revealed that members of the Lrp family of transcriptional regulators are widely distributed among prokaryotes, both bacteria and archaea. The archetype Leucine-responsive Regulatory Protein from Escherichia coli is a global regulator involved in modulating a variety of metabolic functions, including the catabolism and anabolism of amino acids as well as pili synthesis. Most Lrp homologues, however, appear to act as specific regulators of amino acid metabolism-related genes. Like most prokaryotic transcriptional regulators, Lrp-like regulators consist of a DNA-binding domain and a ligand-binding domain. The crystal structure of the Pyrococcus furiosus LrpA revealed an N-terminal domain with a common helix–turn–helix fold, and a C-terminal domain with a typical αβ-sandwich fold. The latter regulatory domain constitutes a novel ligand-binding site and has been designated RAM. Database analysis reveals that the RAM domain is present in many prokaryotic genomes, potentially encoding (1) Lrp-homologues, when fused to a DNA-binding domain (2) enzymes, when fused as a potential regulatory domain to a catalytic domain, and (3) stand-alone RAM modules with unknown function. The architecture of Lrp regulators with two distinct domains that harbour the regulatory (effector-binding) site and the active (DNA-binding) site, and their separation by a flexible hinge region, suggests a general allosteric switch of Lrp-like regulators.