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Selective targeting of indel‐inferred differences in spatial structures of highly homologous proteins
Author(s) -
Cherkasov Artem,
Nandan Devki,
Reiner Neil E.
Publication year - 2005
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.20391
Subject(s) - biology , indel , virulence , genetics , peptide sequence , human pathogen , sequence alignment , computational biology , virulence factor , gene , sequence (biology) , genotype , single nucleotide polymorphism
Abstract Recent findings have shown that the protein elongation factor‐1α (EF‐1α) from the eukaryotic pathogen Leishmania donovani possesses virulence properties. This was unexpected, since it has greater than 80% sequence identity with its human homologue. Given that EF‐1α is essential for cell survival, in principle, it can be considered an attractive drug target. However, the challenge is to be able to selectively target the protein so as not to affect function of the human homologue. While a limited number of discrete differences were scattered throughout the sequence, most of the difference between these 2 homologues could be attributed to a 12–amino acid insert present in human EF‐1α and absent from the leishmania sequence. In the present study, we modeled the spatial differences in structures of human and L. donovani EF‐1α's inferred by this insertion–deletion (or “indel”). The protein models were used to develop antibodies directed specifically toward the deletion region of the pathogen protein. The strategy described allowed successful selective targeting of this putative leishmania virulence factor while avoiding recognition of the highly similar human EF‐1α homologue. These findings may establish a new strategy for the development of antagonists directed against certain pathogenic targets having close human homologues. Proteins 2005 © 2005 Wiley‐Liss, Inc.