1f6t
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(New page: 200px<br /> <applet load="1f6t" size="450" color="white" frame="true" align="right" spinBox="true" caption="1f6t, resolution 1.92Å" /> '''STRUCTURE OF THE NU...)
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Revision as of 11:56, 8 November 2007
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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 with MG and TBD as ligands. Active as Nucleoside-diphosphate kinase, with EC number 2.7.4.6 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 Thu Nov 8 14:02:19 2007
Categories: Dictyostelium discoideum | Nucleoside-diphosphate kinase | Single protein | Boretto, J. | Canard, B. | Deville-Bonne, D. | Guerreiro, C. | Janin, J. | Sarfati, S. | Schneider, B. | Veron, M. | MG | TBD | Anti-hiv nucleoside analogue | Boranophosphate | Crystallography | Nucleoside diphosphate kinase | Phosphorylation
