A preliminary 3-D model of the tertiary fold of the polymerase domain of HIV-1 reverse transcriptase.
Development of a 3-D model of the reverse transcriptase from type 1 human immunodeficiency virus (HIV-1 RT), a key enzyme in the pathogenesis of the virus, presents a significant challenge. Three-dimensional structural information is not available for any close homolog, the only 3-D structural data being that of the Klenow fragment (KF) of Escherichia coli DNA polymerase I, for which coordinates of only the alpha-carbons are available. A recently published study of the sequences of a large number of polymerases led to the identification of three common sequence patterns, nominally motif A, motif B and motif C, and to the hypothesis that the various DNA and RNA polymerases including E. coli DNA polymerase I and HIV-1 RT share a common structural motif around their respective polymerase active sites. The preliminary results of recent structural studies on two other polymerases also support this hypothesis. Based on the assumption of structural homology in the active site regions of their polymerase domains, the HIV-1 RT and KF sequences were aligned using pattern-based secondary structure predictions as a guide and motifs A, B and C as 'anchor points'. However, as suggested by the results of chemical modification experiments, it was assumed that the order of the motifs in KF, viz. A, B and C, differed from that of the related motifs A, C and B' in HIV-1 RT, a rearrangement that could have been brought about by an exon shuffling type of mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)
Narasimhan
L S
LS
Upjohn Laboratories, Kalamazoo, MI 49001.
Maggiora
G M
GM
D000595:Amino Acid Sequence; D001665:Binding Sites; D004256:DNA Polymerase I / Q000737:chemistry; D004926:Escherichia coli / Q000201:enzymology; D015497:HIV-1 / Q000201:enzymology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D005810:Multigene Family; D010446:Peptide Fragments / Q000737:chemistry*; D011487:Protein Conformation; D012194:RNA-Directed DNA Polymerase / Q000737:chemistry*; D016415:Sequence Alignment / Q000379:methods
D010446:Peptide Fragments; D012194:RNA-Directed DNA Polymerase; D004256:DNA Polymerase I