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Mechanism for attenuation of DNA binding by MarR family transcriptional regulators by small molecule ligands.
J Mol Biol. 2009 Jul 31; 390(5):1019-29.JM

Abstract

Members of the multiple antibiotic resistance regulator (MarR) family control gene expression in a variety of metabolic processes in bacteria and archaea. Hypothetical uricase regulator (HucR), which belongs to the ligand-responsive branch of the MarR family, regulates uricase expression in Deinococcus radiodurans by binding a shared promoter region between uricase and HucR genes. We show here that HucR responds only to urate and, to a lesser extent, to xanthine by attenuated DNA binding, compared to other intermediates of purine degradation. Using molecular-dynamics-guided mutational analysis, we identified the ligand-binding site in HucR. Electrophoretic mobility shift assays and intrinsic Trp fluorescence have identified W20 from the N-terminal helix and R80 from helix 3, which serves as a scaffold for the DNA recognition helix, as being essential for ligand binding. Using structural data combined with in silico and in vitro analyses, we propose a mechanism for the attenuation of DNA binding in which a conformational change initiated by charge repulsion due to a bound ligand propagates to DNA recognition helices. This mechanism may apply generally to MarR homologs that bind anionic phenolic ligands.

Authors+Show Affiliations

Department of Biological Sciences, Louisiana State University, Baton Rouge, 70803, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

19501097

Citation

Perera, Inoka C., et al. "Mechanism for Attenuation of DNA Binding By MarR Family Transcriptional Regulators By Small Molecule Ligands." Journal of Molecular Biology, vol. 390, no. 5, 2009, pp. 1019-29.
Perera IC, Lee YH, Wilkinson SP, et al. Mechanism for attenuation of DNA binding by MarR family transcriptional regulators by small molecule ligands. J Mol Biol. 2009;390(5):1019-29.
Perera, I. C., Lee, Y. H., Wilkinson, S. P., & Grove, A. (2009). Mechanism for attenuation of DNA binding by MarR family transcriptional regulators by small molecule ligands. Journal of Molecular Biology, 390(5), 1019-29. https://doi.org/10.1016/j.jmb.2009.06.002
Perera IC, et al. Mechanism for Attenuation of DNA Binding By MarR Family Transcriptional Regulators By Small Molecule Ligands. J Mol Biol. 2009 Jul 31;390(5):1019-29. PubMed PMID: 19501097.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanism for attenuation of DNA binding by MarR family transcriptional regulators by small molecule ligands. AU - Perera,Inoka C, AU - Lee,Yong-Hwan, AU - Wilkinson,Steven P, AU - Grove,Anne, Y1 - 2009/06/06/ PY - 2009/04/23/received PY - 2009/05/28/revised PY - 2009/06/01/accepted PY - 2009/6/9/entrez PY - 2009/6/9/pubmed PY - 2009/7/29/medline SP - 1019 EP - 29 JF - Journal of molecular biology JO - J Mol Biol VL - 390 IS - 5 N2 - Members of the multiple antibiotic resistance regulator (MarR) family control gene expression in a variety of metabolic processes in bacteria and archaea. Hypothetical uricase regulator (HucR), which belongs to the ligand-responsive branch of the MarR family, regulates uricase expression in Deinococcus radiodurans by binding a shared promoter region between uricase and HucR genes. We show here that HucR responds only to urate and, to a lesser extent, to xanthine by attenuated DNA binding, compared to other intermediates of purine degradation. Using molecular-dynamics-guided mutational analysis, we identified the ligand-binding site in HucR. Electrophoretic mobility shift assays and intrinsic Trp fluorescence have identified W20 from the N-terminal helix and R80 from helix 3, which serves as a scaffold for the DNA recognition helix, as being essential for ligand binding. Using structural data combined with in silico and in vitro analyses, we propose a mechanism for the attenuation of DNA binding in which a conformational change initiated by charge repulsion due to a bound ligand propagates to DNA recognition helices. This mechanism may apply generally to MarR homologs that bind anionic phenolic ligands. SN - 1089-8638 UR - https://www.unboundmedicine.com/medline/citation/19501097/Mechanism_for_attenuation_of_DNA_binding_by_MarR_family_transcriptional_regulators_by_small_molecule_ligands_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-2836(09)00679-2 DB - PRIME DP - Unbound Medicine ER -