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

PDB id:

6r4t

Name:

Replication

Title:

Crystal structure of the pri1 subunit of human primase bound to vidarabine triphosphate

Structure:

DNA primase small subunit. Chain: a, d. Synonym: DNA primase 49 kda subunit,p49. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: prim1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Expression_system_variant: rosetta2

Resolution:

2.35Å R-factor: 0.211 R-free: 0.239

Authors:

M.L.Kilkenny,L.Pellegrini

Key ref:

S.Holzer et al. (2019). Structural Basis for Inhibition of Human Primase by Arabinofuranosyl Nucleoside Analogues Fludarabine and Vidarabine. ACS Chem Biol, 14, 1904-1912. PubMed id: 31479243 DOI: 10.1021/acschembio.9b00367

Date:

24-Mar-19 Release date: 11-Sep-19

Protein chains

P49642  (PRI1_HUMAN) -  DNA primase small subunit from Homo sapiens

Seq: 420 a.a.

Struc: 384 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.7.102 - Dna primase aep.
• Reaction:
  1. ssDNA + n NTP = ssDNA/pppN(pN)n-1 hybrid + (n-1) diphosphate
  2. ssDNA + n dNTP = ssDNA/pppdN(pdN)n-1 hybrid + (n-1) diphosphate

ssDNA + n NTP (Bound ligand (Het Group name = HEJ) matches with 65.62% similarity) = ssDNA/pppN(pN)n-1 hybrid + (n-1) diphosphate

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1021/acschembio.9b00367

ACS Chem Biol 14:1904-1912 (2019)

PubMed id: 31479243

Structural Basis for Inhibition of Human Primase by Arabinofuranosyl Nucleoside Analogues Fludarabine and Vidarabine.

S.Holzer, N.J.Rzechorzek, I.R.Short, M.Jenkyn-Bedford, L.Pellegrini, M.L.Kilkenny.

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.