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Crystal structure of the effector-binding domain of DasR (DasR-EBD) in complex with N-acetylglucosamine-6-phosphate
Structural highlights
FunctionDASR_STRCO Global regulator that is part of the nutrient-sensing system. In the absence of N-acetylglucosamine 6-P, represses the phosphotransferase system (PTS) specific for the uptake of N-acetylglucosamine (PTSNag), and genes involved in the metabolism of chitin, as well as several genes involved in development, thereby linking carbon availability to morphogenesis. Binds to the DNA consensus sequence 5'-ACTGGTCTAGACCACT-3'.[1] [2] Publication Abstract from PubMedSmall molecule effectors regulate gene transcription in bacteria by altering the DNA-binding affinities of specific repressor proteins. Although the GntR proteins represent a large family of bacterial repressors, only little is known about the allosteric mechanism that enables their function. DasR from Streptomyces coelicolor belongs to the GntR/HutC subfamily and specifically recognises operators termed DasR-responsive elements (dre-sites). Its DNA-binding properties are modulated by phosphorylated sugars. Here, we present several crystal structures of DasR, namely of dimeric full-length DasR in the absence of any effector and of only the effector-binding domain (EBD) of DasR without effector or in complex with glucosamine-6-phosphate (GlcN-6-P) and N-acetylglucosamine-6-phosphate (GlcNAc-6-P). Together with molecular dynamics (MD) simulations and a comparison with other GntR/HutC family members these data allowed for a structural characterisation of the different functional states of DasR. Allostery in DasR and possibly in many other GntR/HutC family members is best described by a conformational selection model. In ligand-free DasR, an increased flexibility in the EBDs enables the attached DNA-binding domains (DBD) to sample a variety of different orientations and among these also a DNA-binding competent conformation. Effector binding to the EBDs of DasR significantly reorganises the atomic structure of the latter. However, rather than locking the orientation of the DBDs, the effector-induced formation of beta-strand beta* in the DBD-EBD-linker segment merely appears to take the DBDs 'on a shorter leash' thereby impeding the 'downwards' positioning of the DBDs that is necessary for a concerted binding of two DBDs of DasR to operator DNA. Crystal Structures of the Global Regulator DasR from Streptomyces coelicolor: Implications for the Allosteric Regulation of GntR/HutC Repressors.,Fillenberg SB, Friess MD, Korner S, Bockmann RA, Muller YA PLoS One. 2016 Jun 23;11(6):e0157691. doi: 10.1371/journal.pone.0157691., eCollection 2016. PMID:27337024[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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