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Title: Crystal Structures of the Response Regulator DosR From Mycobacterium Tuberculosis Suggest a Helix Rearrangement Mechanism for Phosphorylation Activation

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 {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}){sub 4} topology instead of the canonical ({beta}{alpha}){sub 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 helixmore » rearrangement mechanism.« less
Authors:
; ; ;
Publication Date:
OSTI Identifier:
953608
Report Number(s):
SLAC-REPRINT-2009-275
Journal ID: ISSN 0022-2836; JMOBAK; TRN: US201002%%1436
DOE Contract Number:
AC02-76SF00515
Resource Type:
Journal Article
Resource Relation:
Journal Name: J. Mol. Biol. 378:227,2008; Journal Volume: 378; Journal Issue: 1
Research Org:
Stanford Linear Accelerator Center (SLAC)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; CRYSTAL STRUCTURE; DIMERS; FLEXIBILITY; MYCOBACTERIUM TUBERCULOSIS; OXYGEN; PHOSPHORYLATION; RESIDUES; RESOLUTION; TOPOLOGY; TUBERCULOSIS Other,OTHER, BIO