ZIB

Hits per page

hits 1 - 2 | 2 hits

Sorting

Electronic Resource

Review of HIV-1 reverse transcriptase three-dimensional structure: Implications for drug design (1993)

Nanni, Raymond G. ; Ding, Jianping ; Jacobo-Molina, Alfredo ; [et al.]

Springer

Perspectives in drug discovery and design 1 (1993), S. 129-150

add to mindlist on the mindlist

Details

ISSN: 1573-9023

Keywords: AIDS ; Antiviral agents ; Drug resistance ; Polymerase structure ; Protein-nucleic acid interactions ; Reverse transcriptase inhibitors

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Summary Two recent X-ray crystallographic studies have resulted in the three-dimensional structure determination of the reverse transcriptase (RT) enzyme from the human immunodeficiency virus type 1 (HIV-1) [Kohlstaedt et al., Science, 256 (1992) 1783; Jacobo-Molina et al., Proc. Natl. Acad. Sci. USA, 90 (1993) 6320]. This report reviews the structure of the reverse transcriptase heterodimer and provides a detailed description of the folding and topology of the individual subdomains. The interactions of the enzyme with bound template- primer are highlighted. Structure-function relationships have been established and are discussed for several conserved sequence motifs located within the enzyme. Each of these motifs is found to interact significantly with template-primer during the polymerization process. This review integrates the findings of both structure determinations, in particular, to relate these structures to strategies for drug design and development. The structures of both the nucleoside and nonnucleoside inhibitor binding sites are described, and the spatial relationship between the two sites is discussed in light of some novel possibilities for drug development. The first indication of an HIV-1 RT drug-resistant mutation manifested in the p51 subunit is presented. This mutation is located in a region of p51 that is proximal to the nonnucleoside binding pocket. The mechanisms of HIV-1 RT inhibition by both nucleoside and nonnucleoside classes of inhibitors are discussed in relation to the structure of the enzyme. In addition, the implications of the structure for understanding and avoiding the development of resistance of HIV-1 reverse transcriptase to antiviral inhibitors are discussed.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF02171659

Permalink

Library	Location	Call Number	Volume/Issue/Year	Availability

Others were also interested in ...

Paper (German National Licenses)

Fulltext

Electronic Resource

Buried surface analysis of HIV-1 reverse transcriptase p66/p51 heterodimer and its interaction with dsDNA template/primer (1994)

Ding, Jianping ; Jacobo-Molina, Alfredo ; Tantillo, Chris ; [et al.]

Chicester [u.a.] : Wiley-Blackwell

Journal of Molecular Recognition 7 (1994), S. 157-161

add to mindlist on the mindlist

Details

ISSN: 0952-3499

Keywords: Polymerase ; AIDS ; Crystallography ; DNA-protein interactions ; Chemistry ; Biochemistry and Biotechnology

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Medicine

Notes: The p66/p51 human immunodeficiency virus type 1 reverse transcriptase is a heterodimer with identical N-terminal amino acid sequences. The enzyme contains two polymerization domains and one RNase H domain, which is located at the C-terminus of the p66 subunit. Both polymerization domains fold into four individual subdomains that are not arranged in a similar fashion, forming an unusually asymmetric dimer. The complexity of the RT p66/p51 heterodimer structure is simplified using solvent-accessibility surface areas to describe the buried surface area of contact among the different subdomains. In addition, the RT/DNA contacts in the recently published RT/DNA/Fab structure. [Jacobo-Molina et al., Proc. Natl Acad. Sci. USA 90, 6320-6324 (1993)] are described using the same approach. Finally, the RT/DNA complex is compared with other dimeric DNA-binding proteins. It was found that the size of the protein and the extent of the dimer interface were not directly related to the extent of contact between the protein and the DNA. Furthermore, RT, the only protein that is not a sequence specific DNA binding protein in this analysis, had the largest surface of interaction with the nucleic acid.

Additional Material: 1 Ill.