NORMAL GENOMIC

• Rigali S, Derouaux A, Giannotta F, Dusart J
• Subdivision of the helix-turn-helix GntR family of bacterial regulators inthe FadR, HutC, MocR, and YtrA subfamilies.
• J Biol Chem. 2002; 277: 12507-15
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• Haydon and Guest (Haydon, D. J, and Guest, J. R. (1991) FEMS Microbiol.Lett. 63, 291-295) first described the helix-turn-helix GntR family ofbacterial regulators. They presented them as transcription factors sharinga similar N-terminal DNA-binding (d-b) domain, but they observednear-maximal divergence in the C-terminal effector-binding andoligomerization (E-b/O) domain. To elucidate this C-terminalheterogeneity, structural, phylogenetic, and functional analyses wereperformed on a family that now comprises about 270 members. Ourcomparative study first focused on the C-terminal E-b/O domains and nexton DNA-binding domains and palindromic operator sequences, has classifiedthe GntR members into four subfamilies that we called FadR, HutC, MocR,and YtrA. Among these subfamilies a degree of similarity of about 55% wasobserved throughout the entire sequence. Structure/function associationswere highlighted although they were not absolutely stringent. Theconsensus sequences deduced for the DNA-binding domain were slightlydifferent for each subfamily, suggesting that fusion between the D-b andE-b/O domains have occurred separately, with each subfamily having its ownD-b domain ancestor. Moreover, the compilation of the known or predictedpalindromic cis-acting elements has highlighted different operatorsequences according to our subfamily subdivision. The observed C-terminalE-b/O domain heterogeneity was therefore reflected on the DNA-bindingdomain and on the cis-acting elements, suggesting the existence of a tightlink between the three regions involved in the regulating process.

• van Aalten DM, DiRusso CC, Knudsen J, Wierenga RK
• Crystal structure of FadR, a fatty acid-responsive transcription factorwith a novel acyl coenzyme A-binding fold.
• EMBO J. 2000; 19: 5167-77
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• FadR is a dimeric acyl coenzyme A (acyl CoA)-binding protein andtranscription factor that regulates the expression of genes encoding fattyacid biosynthetic and degrading enzymes in Escherichia coli. Here, the 2.0A crystal structure of full-length FadR is described, determined usingmulti-wavelength anomalous dispersion. The structure reveals a dimer and atwo-domain fold, with DNA-binding and acyl-CoA-binding sites located in anN-terminal and C-terminal domain, respectively. The N-terminal domaincontains a winged helix-turn-helix prokaryotic DNA-binding fold.Comparison with known structures and analysis of mutagenesis datadelineated the site of interaction with DNA. The C-terminal domain has anovel fold, consisting of a seven-helical bundle with a crossovertopology. Careful analysis of the structure, together with mutational andbiophysical data, revealed a putative hydrophobic acyl-CoA-binding site,buried in the core of the seven-helical bundle. This structure aids inunderstanding FadR function at a molecular level, provides the firststructural scaffold for the large GntR family of transcription factors,which are keys in the control of metabolism in bacterial pathogens, andcould thus be a possible target for novel chemotherapeutic agents.