Tuberculosis Challenge – Alternate Target
Tuberculosis (TB) is a disease that affects millions of people. We have posted a protein drug target puzzle previously on this topic. In our continued effort to make a dent in this disease, we have also partnered with the Sacchettini lab at Texas A&M University to post another drug target puzzle for TB.
The Sacchettini lab is working in collaboration with other groups on understanding biology and virulence factors of tuberculosis bacteria. The ability of Mycobacterium tuberculosis, which causes TB, to survive inside the host depends on sensing the environment and launching appropriate responses to stimuli. This means that specific protein production levels are strictly controlled and tuned. The machinery and the players of this carefully orchestrated battle against our immune system are poorly characterized. In general, protein production levels could be regulated on multiple levels and by different means. One of the ways involves small non-coding RNA molecules which aid in efficient translation of some mRNAs into proteins and the degradation of others. In pathogenic bacteria specifically, the regulation of production of the proteins required for virulence and intracellular survival has been shown to depend on small RNAs. Reviewed here (Oliva G., Sahr T., Buchrieser C. (2015). Small RNAs, 5’ UTR elements and RNA-binding proteins in intracellular bacteria: impact on metabolism and virulence. FEMS Microbiol. Rev. 39 331–349. :
To carry out their missions, small RNAs require protective chaperon protein – Hfq. Specifically, the protein structure adopts an Sm like fold composed of 6 subunits forming a homo-hexameric ring. Hfq and Sm proteins have been identified in numerous bacteria, yet no known homologs have been annotated in Mycobacterium tuberculosis genome. Through careful examination of secondary structure patterns predictions of the Mycobacterium tuberculosis proteome, Rv3208A has been proposed as a possible Hfq candidate.
If we were able to solve the structure, it would mean that we learn about machinery which has been shown to be important for virulence in other pathogens but is not characterized in Mycobacterium yet. By targeting this RNA chaperon protein, instrumental to any small RNA mediated responses, scientists can prevent Mycobacterium tuberculosis from survival inside human host.
Right now, the protein has been crystallized and diffraction data are available, but none of the models that scientists have created have helped to solve the phase and build the structure. By posting this protein, we are hoping that everyone can come up with a model that will help resolve the structure. As always, we are committed to publishing the work and sharing models created by Foldit players. Lets make a dent in TB!( Posted by free_radical 76 2490 | Tue, 11/29/2016 - 19:29 | 6 comments )