Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 378, Issue 1, Pages 227-242Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2008.02.029
Keywords
response regulators; NarL; latent tuberculosis; protein conformational changes
Categories
Funding
- Howard Hughes Medical Institute Funding Source: Medline
- NCI NIH HHS [R01 CA065656-08, R01 CA065656, CA65656] Funding Source: Medline
- NIAID NIH HHS [R21 AI047744, R01 AI047744, AI47744] Funding Source: Medline
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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. p unphosphorylated DosR at 2.2 angstrom resolution and its C-terminal DNA-binding domain at 1.7 angstrom 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 (beta alpha)(4) topology instead of the canonical (beta alpha)(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 alpha 10, 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 alpha 10 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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