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1qe1
From Proteopedia
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| - | [[Image:1qe1.gif|left|200px]] | + | [[Image:1qe1.gif|left|200px]] |
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| - | '''CRYSTAL STRUCTURE OF 3TC-RESISTANT M184I MUTANT OF HIV-1 REVERSE TRANSCRIPTASE''' | + | {{Structure |
| + | |PDB= 1qe1 |SIZE=350|CAPTION= <scene name='initialview01'>1qe1</scene>, resolution 2.85Å | ||
| + | |SITE= | ||
| + | |LIGAND= | ||
| + | |ACTIVITY= [http://en.wikipedia.org/wiki/RNA-directed_DNA_polymerase RNA-directed DNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.49 2.7.7.49] | ||
| + | |GENE= | ||
| + | }} | ||
| + | |||
| + | '''CRYSTAL STRUCTURE OF 3TC-RESISTANT M184I MUTANT OF HIV-1 REVERSE TRANSCRIPTASE''' | ||
| + | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1QE1 is a [ | + | 1QE1 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Human_immunodeficiency_virus_type_1_(isolate_bh10) Human immunodeficiency virus type 1 (isolate bh10)]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1QE1 OCA]. |
==Reference== | ==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:[http:// | + | 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:[http://www.ncbi.nlm.nih.gov/pubmed/10468556 10468556] |
[[Category: Human immunodeficiency virus type 1 (isolate bh10)]] | [[Category: Human immunodeficiency virus type 1 (isolate bh10)]] | ||
[[Category: RNA-directed DNA polymerase]] | [[Category: RNA-directed DNA polymerase]] | ||
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[[Category: transferase]] | [[Category: transferase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 13:36:24 2008'' |
Revision as of 11:36, 20 March 2008
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| , resolution 2.85Å | |||||||
|---|---|---|---|---|---|---|---|
| Activity: | RNA-directed DNA polymerase, with EC number 2.7.7.49 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
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). 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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