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| - | [[Image:1j5o.gif|left|200px]] | + | {{Seed}} |
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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'''
| + | ===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.
| + | The line below this paragraph, {{ABSTRACT_PUBMED_10468556}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 10468556 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_10468556}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Protein-dna complex]] | | [[Category: Protein-dna complex]] |
| | [[Category: Reverse transcriptase]] | | [[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 Tue Jul 1 14:32:21 2008'' |
Revision as of 11:32, 1 July 2008
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
Page seeded by OCA on Tue Jul 1 14:32:21 2008
