Selective targeting of indel-inferred differences in spatial structures of homologous proteins.
The eukaryotic pathogen Leishmania donovani possesses a housekeeping protein Elongation-Factor-1alpha (EF-1alpha) which has been found to be unexpectedly involved in the pathogen's virulence. Because it is associated with virulence and essential for cell survival, this protein is an attractive choice for drug targeting; however, its sequence is highly similar (> 80% sequence identity) to that of its human homolog, rendering it a risky choice for a drug target. The chief difference between these two proteins has been found to be a 12 amino acid sequence present in human EF-1alpha but absent from leishmania EF-1alpha. Furthermore, it has been shown that this 12 amino acid insert in the human sequence corresponds to a hairpin loop on the surface of the protein. In this study, we searched for those spatial features in leishmania EF-1alpha that are impacted or obscured by the extra hairpin loop in the human counterpart. We have also conducted a large-scale in silico screening for small molecules that could plausibly bind to these protein features. While experimental evidence is required to verify our results, our findings thus far appear to support this approach as a new strategy for the development of antagonists against pathogenic targets having close human homologs.
Li
Yvonne Y
YY
CIHR/MSFHR Strategic Training Program in Bioinformatics, University of British Columbia, 570 West 7th Avenue, Vancouver, British Columbia, V5Z 4S6, Canada. yli@bcgsc.ca
Jones
Steven J M
SJ
Cherkasov
Artem
A
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D007893:Leishmania donovani / Q000378:metabolism*; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry*; D020648:Peptide Elongation Factor 1 / Q000737:chemistry*; D011485:Protein Binding; D016415:Sequence Alignment / Q000379:methods*; D020539:Sequence Analysis, Protein / Q000379:methods*; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D014157:Transcription Factors / Q000737:chemistry*
D009687:Nuclear Proteins; D020648:Peptide Elongation Factor 1; D014157:Transcription Factors