A transposition of the reverse transcriptase gene reveals unexpected structural homology to E. coli DNA polymerase I.
The rational design of antiviral agents targeting the reverse transcriptase (RT) of the human immunodeficiency virus (HIV) would greatly benefit from a more intimate knowledge of the structure of RT. Until now, the degree of sequence similarity between RT and E. coli DNA polymerase I (Pol I) has been thought to be confined to several small regions, suggesting little basis for homology molecular modeling. However, we have found that a region in the C terminal of the RT polymerase domain is homologous to a central region of Pol I that lies between the universal polymerase motifs A and C (specifically, helices N-O-P of the Pol I crystal structure); a single transposition closely aligns the RT and Pol I genes, revealing a similar domain structure with 20% residue identity, as well as the possible structural correlates of several RNA-dependent polymerase motifs. The RT from Myxococcus xanthus (a bacterium believed to have diverged from other species 2 billion years ago), if similarly transposed, shows homology to both HIV-1 and E. coli, suggesting the possibility of a very ancient divergence between the RT and Pol I polymerase genes. A second even more significant match to this E. coli region was found in the retroviral ribonuclease H (RNase H) domain, and corresponds precisely to a region that has been aligned by previous investigators with the E. coli RNase H, suggesting that Pol I helices O and P are homologous to helices A and D of the RNase H crystal structure, respectively. These results are consistent with a modular theory of molecular evolution.
Taylor
E W
EW
Department of Medicinal Chemistry, College of Pharmacy, University of Georgia, Athens 30602.
Jaakkola
J
J
D000595:Amino Acid Sequence; D004256:DNA Polymerase I / Q000235:genetics*; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics*; D015497:HIV-1 / Q000201:enzymology / Q000235:genetics*; D008961:Models, Structural; D008969:Molecular Sequence Data; D016941:Myxococcus xanthus / Q000201:enzymology / Q000235:genetics*; D011487:Protein Conformation; D012194:RNA-Directed DNA Polymerase / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid
D012194:RNA-Directed DNA Polymerase; D004256:DNA Polymerase I