当前位置： SCI文献检索 > JOURNAL OF BIOMEDICAL SCIENCE期刊下所有文献 > Structural analysis of reverse transcriptase mutations at codon 215 explains the predominance of T215Y over T215F in HIV-1 variants selected under antiretroviral therapy.

Structural analysis of reverse transcriptase mutations at codon 215 explains the predominance of T215Y over T215F in HIV-1 variants selected under antiretroviral therapy.

Abstract：

:Mutations at codon 215 of HIV-1 reverse transcriptase (RT) confer resistance to nucleoside analogs through RT-catalyzed ATP-dependent phosphorolysis. We showed that mutation T215Y is predominant over T215F (respectively 38.8 vs. 7.04% of 7312 sequences from a cohort of patients receiving antiretroviral therapy in France). Ambiguous mixtures at codon 215 (e.g. TNYS and TFSI) were resolved by cloning and sequencing representative clinical samples. Mutation T215F was preferentially associated with K70R (>71%), D67N (>73%) and K219Q/E/N (>76%), whereas T215Y was associated with M41L (>84%) and L210W (>58%). A similar distribution was observed with RT sequences stored in the Stanford HIV Drug Resistance Database. The structural background of these two distinct mutational patterns was investigated by molecular modeling of ATP-mutant RT complexes, on the basis of known ATP-protein interactions. We found that the aromatic side chain of tyrosine (Y)--but not phenylalanine (F)--optimally stacked with the adenine ring of ATP. Mutation L210W further stabilized this aromatic pi-pi stacking interaction, increasing the affinity of the T215Y/L210W double mutant for ATP. Overall, this study provides a biochemical basis accounting for the evolutionary pathway of T215 mutations in HIV-1 RT, leading to the preferential selection of T215Y vs. T215F.

journal_name

J Biomed Sci

journal_title

Journal of biomedical science

authors

Yahi N,Fantini J,Henry M,Tourrès C,Tamalet C

doi

10.1007/s11373-005-9011-4

keywords:

subject

Has Abstract

pub_date

2005-10-01 00:00:00

pages

701-10

issue

5

eissn

1021-7770

issn

1423-0127

journal_volume

12

pub_type

杂志文章

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