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Crystal Structure of Fad35R from Mycobacterium tuberculosis H37Rv in the Apo-State
Authors:Appu Kumar Singh  Babu Manjasetty  Balasubramani GL  Sukirte Koul  Abhishek Kaushik  Mary Krishna Ekka  Vijay Singh  S Kumaran
Institution:1Council of Scientific and Industrial Research (CSIR), Institute of Microbial Technology, G.N.Ramachandran Protein Centre, Chandigarh, 160036, India;2European Molecular Biology Laboratory, Grenoble Outstation, 38000, France;3Unit for Virus Host-Cell Interactions, Univ. Grenoble Alpes-EMBL-CNRS, 38000, France;University of South Florida College of Medicine, UNITED STATES
Abstract:Fad35R from Mycobacterium tuberculosis binds to the promoter site of Fad35 operon and its DNA binding activities are reduced in the presence of tetracycline and palmitoyl-CoA. We resolved the crystal structure of Fad35R using single-wavelength anomalous diffraction method (SAD). Fad35R comprises canonical DNA binding domain (DBD) and ligand binding domain (LBD), but displays several distinct structural features. Two recognition helices of two monomers in the homodimer are separated by ~ 48 Å and two core triangle-shaped ligand binding cavities are well exposed to solvent. Structural comparison with DesT and QacR structures suggests that ligand binding-induced movement of α7, which adopts a straight conformation in the Fad35R, may be crucial to switch the conformational states between repressive and derepressive forms. Two DBDs are packed asymmetrically, creating an alternative dimer interface which coincides with the possible tetramer interface that connects the two canonical dimers. Quaternary state of alternative dimer mimics a closed-state structure in which two recognition helices are distanced at ~ 35 Å and ligand binding pockets are inaccessible. Results of biophysical studies indicate that Fad35R has the propensity to oligomerize in solution in the presence of tetracycline. We present the first structure of a FadR homologue from mycobacterium and the structure reveals DNA and ligand binding features of Fad35R and also provides a view on alternative quaternary states that mimic open and closed forms of the regulator.
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