Structural highlights
Function
[DBH_MYCTU] Histone-like DNA-binding protein which is capable of wrapping DNA to stabilize it, and thus to prevent its denaturation under extreme environmental conditions. Binds DNA non-specifically. Induces lymphoproliferation, particularly in health tuberculin reactors, and is immunogenic. Maybe involved in pathogenesis of inflammatory bowel disease (IBD) in patients with ulcerative colitis and Crohn disease (CD). Bound by anti-neutrophil cytoplasmic antibodies (pANCA), which are a hallmark of IBD. The binding is due to pANCA directed against HIST1H1D cross-reacting with DBH epitopes. In CD, target of a strong IgA response.[1] [2]
Publication Abstract from PubMed
The nucleoid-associated protein HU plays an important role in maintenance of chromosomal architecture and in global regulation of DNA transactions in bacteria. Although HU is essential for growth in Mycobacterium tuberculosis (Mtb), there have been no reported attempts to perturb HU function with small molecules. Here we report the crystal structure of the N-terminal domain of HU from Mtb. We identify a core region within the HU-DNA interface that can be targeted using stilbene derivatives. These small molecules specifically inhibit HU-DNA binding, disrupt nucleoid architecture and reduce Mtb growth. The stilbene inhibitors induce gene expression changes in Mtb that resemble those induced by HU deficiency. Our results indicate that HU is a potential target for the development of therapies against tuberculosis.
Targeting Mycobacterium tuberculosis nucleoid-associated protein HU with structure-based inhibitors.,Bhowmick T, Ghosh S, Dixit K, Ganesan V, Ramagopal UA, Dey D, Sarma SP, Ramakumar S, Nagaraja V Nat Commun. 2014 Jun 11;5:4124. doi: 10.1038/ncomms5124. PMID:24916461[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Cohavy O, Harth G, Horwitz M, Eggena M, Landers C, Sutton C, Targan SR, Braun J. Identification of a novel mycobacterial histone H1 homologue (HupB) as an antigenic target of pANCA monoclonal antibody and serum immunoglobulin A from patients with Crohn's disease. Infect Immun. 1999 Dec;67(12):6510-7. PMID:10569769
- ↑ Prabhakar S, Annapurna PS, Jain NK, Dey AB, Tyagi JS, Prasad HK. Identification of an immunogenic histone-like protein (HLPMt) of Mycobacterium tuberculosis. Tuber Lung Dis. 1998;79(1):43-53. PMID:10645441 doi:http://dx.doi.org/10.1054/tuld.1998.0004
- ↑ Bhowmick T, Ghosh S, Dixit K, Ganesan V, Ramagopal UA, Dey D, Sarma SP, Ramakumar S, Nagaraja V. Targeting Mycobacterium tuberculosis nucleoid-associated protein HU with structure-based inhibitors. Nat Commun. 2014 Jun 11;5:4124. doi: 10.1038/ncomms5124. PMID:24916461 doi:http://dx.doi.org/10.1038/ncomms5124
