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1j5o

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[[Image:1j5o.gif|left|200px]]
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{{STRUCTURE_1j5o| PDB=1j5o | SCENE= }}
{{STRUCTURE_1j5o| PDB=1j5o | SCENE= }}
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'''CRYSTAL STRUCTURE OF MET184ILE MUTANT OF HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH DOUBLE STRANDED DNA TEMPLATE-PRIMER'''
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===CRYSTAL STRUCTURE OF MET184ILE MUTANT OF HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH DOUBLE STRANDED DNA TEMPLATE-PRIMER===
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==Overview==
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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.
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{{ABSTRACT_PUBMED_10468556}}
==About this Structure==
==About this Structure==
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[[Category: Protein-dna complex]]
[[Category: Protein-dna complex]]
[[Category: Reverse transcriptase]]
[[Category: Reverse transcriptase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 1 14:32:21 2008''

Revision as of 11:32, 1 July 2008

Image:1j5o.png

Template:STRUCTURE 1j5o

CRYSTAL STRUCTURE OF MET184ILE MUTANT OF HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH DOUBLE STRANDED DNA TEMPLATE-PRIMER

Template:ABSTRACT PUBMED 10468556

About this Structure

1J5O is a Protein complex structure of sequences from Human immunodeficiency virus 1 and Mus musculus. This structure supersedes the now removed PDB entry 1c9r. 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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