1j5o
From Proteopedia
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| - | | | + | {{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''' | '''CRYSTAL STRUCTURE OF MET184ILE MUTANT OF HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH DOUBLE STRANDED DNA TEMPLATE-PRIMER''' | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1J5O is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. This structure supersedes the now removed PDB entry | + | 1J5O is a [[Protein complex]] structure of sequences from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_1 Human immunodeficiency virus 1] and [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=1c9r 1c9r]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1J5O OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Sarafianos, S G.]] | [[Category: Sarafianos, S G.]] | ||
[[Category: 3tc]] | [[Category: 3tc]] | ||
| - | [[Category: | + | [[Category: Drug resistance]] |
| - | [[Category: | + | [[Category: Hiv]] |
| - | [[Category: | + | [[Category: M184i]] |
| - | [[Category: | + | [[Category: Met184ile]] |
| - | [[Category: | + | [[Category: Protein-dna complex]] |
| - | [[Category: | + | [[Category: Reverse transcriptase]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 20:50:12 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 17:50, 2 May 2008
CRYSTAL STRUCTURE OF MET184ILE MUTANT OF HIV-1 REVERSE TRANSCRIPTASE IN COMPLEX WITH DOUBLE STRANDED DNA TEMPLATE-PRIMER
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
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 Page seeded by OCA on Fri May 2 20:50:12 2008
