1F6T

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

Summary for 1F6T

• Entry DOI: 10.2210/pdb1f6t/pdb
• Related: 1F3F 1LWX
• Descriptor: PROTEIN (NUCLEOSIDE DIPHOSPHATE KINASE), MAGNESIUM ION, 2*-DEOXY-THYMIDINE-5*-ALPHA BORANO DIPHOSPHATE (ISOMER RP), ... (4 entities in total)
• Functional Keywords: nucleoside diphosphate kinase, anti-hiv nucleoside analogue, phosphorylation, boranophosphate, transferase
• Biological source: Dictyostelium discoideum
• Cellular location: Cytoplasm: P22887
• Total number of polymer chains: 3
• Total formula weight: 51722.00

Authors

Guerreiro, C.,Boretto, J.,Janin, J.,Veron, M.,Canard, B.,Schneider, B.,Sarfati, S.,Deville-Bonne, D. (deposition date: 2000-06-23, release date: 2000-09-13, Last modification date: 2024-02-07)

Primary citation

Meyer, P.,Schneider, B.,Sarfati, S.,Deville-Bonne, D.,Guerreiro, C.,Boretto, J.,Janin, J.,Veron, M.,Canard, B.
Structural basis for activation of alpha-boranophosphate nucleotide analogues targeting drug-resistant reverse transcriptase.
EMBO J., 19:3520-3529, 2000

PubMed Abstract: 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.

PubMed: 10899107
DOI: 10.1093/emboj/19.14.3520

Experimental method

X-RAY DIFFRACTION (1.92 Å)