1f6t

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Template:STRUCTURE 1f6t

STRUCTURE OF THE NUCLEOSIDE DIPHOSPHATE KINASE/ALPHA-BORANO(RP)-TDP.MG COMPLEX

Overview

AIDS chemotherapy is limited by inadequate intracellular concentrations of the active triphosphate form of nucleoside analogues, leading to incomplete inhibition of viral replication and the appearance of drug-resistant virus. Drug activation by nucleoside diphosphate kinase and inhibition of HIV-1 reverse transcriptase were studied comparatively. We synthesized analogues with a borano (BH(3)(-)) group on the alpha-phosphate, and found that they are substrates for both enzymes. X-ray structures of complexes with nucleotide diphosphate kinase provided a structural basis for their activation. The complex with d4T triphosphate displayed an intramolecular CH.O bond contributing to catalysis, and the R(p) diastereoisomer of thymidine alpha-boranotriphosphate bound like a normal substrate. Using alpha-(R(p))-boranophosphate derivatives of the clinically relevant compounds AZT and d4T, the presence of the alpha-borano group improved both phosphorylation by nucleotide diphosphate kinase and inhibition of reverse transcription. Moreover, repair of blocked DNA chains by pyrophosphorolysis was reduced significantly in variant reverse transcriptases bearing substitutions found in drug-resistant viruses. Thus, the alpha-borano modification of analogues targeting reverse transcriptase may be of generic value in fighting viral drug resistance.

About this Structure

1F6T is a Single protein structure of sequence from Dictyostelium discoideum. Full crystallographic information is available from OCA.

Reference

Structural basis for activation of alpha-boranophosphate nucleotide analogues targeting drug-resistant reverse transcriptase., Meyer P, Schneider B, Sarfati S, Deville-Bonne D, Guerreiro C, Boretto J, Janin J, Veron M, Canard B, EMBO J. 2000 Jul 17;19(14):3520-9. PMID:10899107 Page seeded by OCA on Fri May 2 15:58:25 2008