Structural highlights
Function
[DOST_MYCTU] Interacts with the two-component regulatory system DevR/DevS (DosR/DosS) involved in onset of the dormancy response. May act as a direct hypoxia sensor (rather than a redox sensor); the normal state is the oxygenated form, while the deoxy form is probably active for phosphate transfer. May be the secondary sensor for CO. Donates a phosphate group to DevR (DosR).[1] [2] [3]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Mycobacterium tuberculosis responds to changes in environmental conditions through a two-component signaling system that detects reduced O(2) tension and NO and CO exposures via the heme-binding GAF domains of two sensory histidine kinases, DosT and DevS, and the transcriptional regulator DosR. We report the first X-ray structure of the DosT heme-bound GAF domain (GAF(DosT)) in both oxy and deoxy forms determined to a resolution of 2.3 A. In GAF(DosT), heme binds in an orientation orthogonal to that in the PAS domains via a highly conserved motif, including invariant H147 as a proximal heme axial ligand. On the distal side, invariant Y169 forms stacking interactions with the heme with its long axis parallel and the plane of the ring orthogonal to the heme plane. In one of the two protein monomers in an asymmetric unit, O(2) binds as a second axial ligand to the heme iron and is stabilized via a H-bond to the OH group of Y169. The structure reveals two small tunnel-connected cavities and a pore on the protein surface that suggest a potential route for the access of O(2) to the sensing pocket. The limited conformational differences observed between differently heme iron-ligated GAF(DosT) monomers in the asymmetric unit may result from crystal lattice limitations since atmospheric oxygen binding likely occurs in the crystal as a result of X-ray-induced Fe(3+) photoreduction during diffraction data collection. Determination of the GAF(DosT) structure sets up a framework in which to address ligand recognition, discrimination, and signal propagation schemes in the heme-based GAF domains of biological sensors.
2.3 A X-ray structure of the heme-bound GAF domain of sensory histidine kinase DosT of Mycobacterium tuberculosis.,Podust LM, Ioanoviciu A, Ortiz de Montellano PR Biochemistry. 2008 Nov 25;47(47):12523-31. PMID:18980385[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Roberts DM, Liao RP, Wisedchaisri G, Hol WG, Sherman DR. Two sensor kinases contribute to the hypoxic response of Mycobacterium tuberculosis. J Biol Chem. 2004 May 28;279(22):23082-7. Epub 2004 Mar 19. PMID:15033981 doi:10.1074/jbc.M401230200
- ↑ Shiloh MU, Manzanillo P, Cox JS. Mycobacterium tuberculosis senses host-derived carbon monoxide during macrophage infection. Cell Host Microbe. 2008 May 15;3(5):323-30. doi: 10.1016/j.chom.2008.03.007. PMID:18474359 doi:10.1016/j.chom.2008.03.007
- ↑ Kumar A, Deshane JS, Crossman DK, Bolisetty S, Yan BS, Kramnik I, Agarwal A, Steyn AJ. Heme oxygenase-1-derived carbon monoxide induces the Mycobacterium tuberculosis dormancy regulon. J Biol Chem. 2008 Jun 27;283(26):18032-9. doi: 10.1074/jbc.M802274200. Epub 2008 , Apr 9. PMID:18400743 doi:10.1074/jbc.M802274200
- ↑ Podust LM, Ioanoviciu A, Ortiz de Montellano PR. 2.3 A X-ray structure of the heme-bound GAF domain of sensory histidine kinase DosT of Mycobacterium tuberculosis. Biochemistry. 2008 Nov 25;47(47):12523-31. PMID:18980385 doi:10.1021/bi8012356
