Crystal structures of the response regulator DosR from Mycobacterium tuberculosis suggest a helix rearrangement mechanism for phosphorylation activation |
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Authors: | Wisedchaisri Goragot Wu Meiting Sherman David R Hol Wim G J |
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Institution: | 1 Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA 2 Biomolecular Structure Center, University of Washington, Seattle, Washington 98195, USA 3 Biomolecular Structure and Design (BMSD) Graduate Program, University of Washington, Seattle, Washington 98195, USA 4 Department of Pathobiology, University of Washington, Seattle, Washington 98195, USA |
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Abstract: | The response regulator DosR is essential for promoting long-term survival of Mycobacterium tuberculosis under low oxygen conditions in a dormant state and may be responsible for latent tuberculosis in one-third of the world's population. Here, we report crystal structures of full-length unphosphorylated DosR at 2.2 Å resolution and its C-terminal DNA-binding domain at 1.7 Å resolution. The full-length DosR structure reveals several features never seen before in other response regulators. The N-terminal domain of the full-length DosR structure has an unexpected (βα)4 topology instead of the canonical (βα)5 fold observed in other response regulators. The linker region adopts a unique conformation that contains two helices forming a four-helix bundle with two helices from another subunit, resulting in dimer formation. The C-terminal domain in the full-length DosR structure displays a novel location of helix α10, which allows Gln199 to interact with the catalytic Asp54 residue of the N-terminal domain. In contrast, the structure of the DosR C-terminal domain alone displays a remarkable unstructured conformation for helix α10 residues, different from the well-defined helical conformations in all other known structures, indicating considerable flexibility within the C-terminal domain. Our structures suggest a mode of DosR activation by phosphorylation via a helix rearrangement mechanism. |
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Keywords: | response regulators NarL latent tuberculosis protein conformational changes |
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