Crystal structure at 3.5 Å resolution of h iv -1 reverse transcriptase complexed with an inhibitor

L. A. Kohlstaed, J. Wang, J. M. Friedman, P. A. Rice, T. A. Steitz

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

A 3.5 angstrom resolution electron density map of the HIV-1 reverse transcriptase heterodimer complexed with nevirapine, a drug with potential for treatment of AIDS, reveals an asymmetric dimer. The polymerase (pol) domain of the 66-kilodalton subunit has a large cleft analogous to that of the Klenow fragment of Escherichia coli DNA polymerase I. However, the 51-kilodalton subunit of identical sequence has no such cleft because the four subdomains of the pol domain occupy completely different relative positions. Two of the four pol subdomains appear to be structurally related to subdomains of the Klenow fragment, including one containing the catalytic site. The subdomain that appears likely to bind the template strand at the pol active site has a different structure in the two polymerases. Duplex A-form RNA-DNA hybrid can be model-built into the cleft that runs between the ribonuclease H and pol active sites. Nevirapine is almost completely buried in a pocket near but not overlapping with the pol active site. Residues whose mutation results in drug resistance have been approximately located.

Original languageEnglish (US)
Title of host publicationStructural Insights into Gene Expression and Protein Synthesis
PublisherWorld Scientific Publishing Co.
Pages254-261
Number of pages8
ISBN (Electronic)9789811215865
ISBN (Print)9789811215858
StatePublished - Jan 1 2020
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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