Proteins with Complex Architecture as Potential Targets for Drug Design: A Case Study of Mycobacterium tuberculosis

Lengthy co-evolution of Homo sapiens and Mycobacterium tuberculosis, the main causative agent of tuberculosis, resulted in a dramatically successful pathogen species that presents considerable challenge for modern medicine. The continuous and ever increasing appearance of multi-drug resistant mycobacteria necessitates the identification of novel drug targets and drugs with new mechanisms of action. However, further insights are needed to establish automated protocols for target selection based on the available complete genome sequences. In the present study, we perform complete proteome level comparisons between M. tuberculosis, mycobacteria, other prokaryotes and available eukaryotes based on protein domains, local sequence similarities and protein disorder. We show that the enrichment of certain domains in the genome can indicate an important function specific to M. tuberculosis. We identified two families, termed pkn and PE/PPE that stand out in this respect. The common property of these two protein families is a complex domain organization that combines species-specific regions, commonly occurring domains and disordered segments. Besides highlighting promising novel drug target candidates in M. tuberculosis, the presented analysis can also be viewed as a general protocol to identify proteins involved in species-specific functions in a given organism. We conclude that target selection protocols should be extended to include proteins with complex domain architectures instead of focusing on sequentially unique and essential proteins only

Identifying variation in resistance to the take-all fungus, Gaeumannomyces graminis var. tritici, between different ancestral and modern wheat species

Background: Ancestral wheat relatives are important sources of genetic diversity for the introduction of novel traits for the improvement of modern bread wheat. In this study the aim was to assess the susceptibility of 34 accessions of the diploid wheat Triticum monococcum (A genome) to Gaeumannomyces graminis var. tritici (Ggt), the causal agent of take-all disease. The second aim was to explore the susceptibility of tetraploid wheat (T. durum) and the B genome progenitor species Aegilops speltoides to Ggt. Results: Field trials, conducted over 5 years, identified seven T. monococcum accessions with a good level of resistance to take-all when exposed to natural inoculum under UK field conditions. All other accessions were highly susceptible or did not exhibit a consistent phenotype across years. DArT marker genotyping revealed that whole genome diversity was not closely related to resistance to take-all within T. monococcum, suggesting that multiple genetic sources of resistance may exist within the species. In contrast the tetraploid wheat cultivars and Ae. speltoides were all highly susceptible to the disease, including those with known elevated levels of benzoxazinoids. Conclusions: The diploid wheat species T. monococcum may provide a genetic source of resistance to take-all disease that could be utilised to improve the performance of T. aestivum in high disease risk situations. This represents an extremely valuable resource to achieve economic and sustainable genetic control of this root disease

A quantitative survey of gravity receptor function in mutant mouse strains.

The purpose of this research was to identify vestibular deficits in mice using linear vestibular evoked potentials (VsEPs). VsEP thresholds, peak latencies, and peak amplitudes from 24 strains with known genetic mutations and 6 inbred background strains were analyzed and descriptive statistics generated for each strain. Response parameters from mutant homozygotes were compared with heterozygote and/or background controls and all strain averages were contrasted to normative ranges. Homozygotes of the following recessive mutations had absent VsEPs at the ages tested: Espn(je), Atp2b2dfw-2J, Spnb4qv-lnd2J, Spnb4qv-3J, Myo7ash1, Tmie(sr), Myo6sv, jc, Pcdh15av-J, Pcdh15av-2J, Pcdh15av-3J, Cdh23v-2J, Sans(js), hr, Kcne1pkr and Pou3f4del. These results suggest profound gravity receptor deficits for these homozygotes, which is consistent with the structural deficits that have been documented for many of these strains. Homozygotes of Catna2cdf, Grid2ho4J, Wnt1sw, qk, and Mbpshi strains and heterozygotes of Grid2lc had measurable VsEPs but one or more response parameters differed from the respective control group (heterozygote or background strain) or were outside normal ranges. For example, qk and Mbpshi homozygotes showed significantly prolonged latencies consistent with the abnormal myelin that has been described for these strains. Prolonged latencies may suggest deficits in neural conduction; elevated thresholds suggest reduced sensitivity, and reduced amplitudes may be suggestive for reduced neural synchrony. One mutation, Otx1jv, had all VsEP response parameters within normal limits--an expected finding because the abnormality in Otxljv is presumably restricted to the lateral semicircular canal. Interestingly, some heterozygote groups also showed abnormalities in one or more VsEP response parameters, suggesting that vestibular dysfunction, although less severe, may be present in some heterozygous animals