PDBsum entry 6r4t

Replication

PDB id: 6r4t

Contents

Protein chains

384 a.a.

Ligands

HEJ ×2

EDO ×2

Metals

_ZN ×2

_MN ×2

Waters ×63

References listed in PDB file

Key reference

• Title: Structural basis for inhibition of human primase by arabinofuranosyl nucleoside analogues fludarabine and vidarabine.
• Authors: S.Holzer, N.J.Rzechorzek, I.R.Short, M.Jenkyn-Bedford, L.Pellegrini, M.L.Kilkenny.
• Ref.: ACS Chem Biol, 2019, 14, 1904-1912. [DOI no: 10.1021/acschembio.9b00367]
• PubMed id: 31479243

Abstract

Nucleoside analogues are widely used in clinical practice as chemotherapy drugs. Arabinose nucleoside derivatives such as fludarabine are effective in the treatment of patients with acute and chronic leukemias and non-Hodgkin's lymphomas. Although nucleoside analogues are generally known to function by inhibiting DNA synthesis in rapidly proliferating cells, the identity of their in vivo targets and mechanism of action are often not known in molecular detail. Here we provide a structural basis for arabinose nucleotide-mediated inhibition of human primase, the DNA-dependent RNA polymerase responsible for initiation of DNA synthesis in DNA replication. Our data suggest ways in which the chemical structure of fludarabine could be modified to improve its specificity and affinity toward primase, possibly leading to less toxic and more effective therapeutic agents.