1qe1

From Proteopedia

Revision as of 12:18, 8 November 2007

CRYSTAL STRUCTURE OF 3TC-RESISTANT M184I MUTANT OF HIV-1 REVERSE TRANSCRIPTASE

Overview

An important component of triple-drug anti-AIDS therapy is 2', 3'-dideoxy-3'-thiacytidine (3TC, lamivudine). Single mutations at residue, 184 of the reverse transcriptase (RT) in HIV cause high-level resistance, to 3TC and contribute to the failure of anti-AIDS combination therapy. We, have determined crystal structures of the 3TC-resistant mutant HIV-1 RT, (M184I) in both the presence and absence of a DNA/DNA template-primer. In, the absence of a DNA substrate, the wild-type and mutant structures are, very similar. However, comparison of crystal structures of M184I mutant, and wild-type HIV-1 RT with and without DNA reveals repositioning of the, template-primer in the M184I/DNA binary complex and other smaller changes, in residues in the dNTP-binding site. On the basis of these structural, results, we developed a model that explains the ability of the, 3TC-resistant mutant M184I to incorporate dNTPs but not the nucleotide, analog 3TCTP. In this model, steric hindrance is expected for NRTIs with, beta- or L- ring configurations, as with the enantiomer of 3TC that is, used in therapy. Steric conflict between the oxathiolane ring of 3TCTP and, the side chain of beta-branched amino acids (Val, Ile, Thr) at position, 184 perturbs inhibitor binding, leading to a reduction in incorporation of, the analog. The model can also explain the 3TC resistance of analogous, hepatitis B polymerase mutants. Repositioning of the template-primer as, observed in the binary complex (M184I/DNA) may also occur in the catalytic, ternary complex (M184I/DNA/3TCTP) and contribute to 3TC resistance by, interfering with the formation of a catalytically competent closed, complex.

About this Structure

1QE1 is a Single protein structure of sequence from Human immunodeficiency virus type 1 (isolate bh10). Active as RNA-directed DNA polymerase, with EC number 2.7.7.49 Full crystallographic information is available from OCA.

Reference

Lamivudine (3TC) resistance in HIV-1 reverse transcriptase involves steric hindrance with beta-branched amino acids., Sarafianos SG, Das K, Clark AD Jr, Ding J, Boyer PL, Hughes SH, Arnold E, Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10027-32. PMID:10468556

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