2ZLF

The Structural Basis for Peptidomimetic Inhibition of Eukaryotic Ribonucleotide Reductase

2ZLF の概要

• エントリーDOI: 10.2210/pdb2zlf/pdb
• 関連するPDBエントリー: 2ZLG
• 分子名称: Ribonucleoside-diphosphate reductase large chain 1, FTLDADF (3 entities in total)
• 機能のキーワード: peptidomimetic inhibition eukaryotic ribonucleotide reductase, allosteric enzyme, atp-binding, cytoplasm, dna replication, nucleotide-binding, oxidoreductase, phosphoprotein
• 由来する生物種: Saccharomyces cerevisiae (Baker's yeast)
• 細胞内の位置: Cytoplasm: P21524
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 100500.86

構造登録者

Xu, H.,Fairman, J.W.,Wijerathna, S.R.,LaMacchia, J.,Kreischer, N.R.,Helmbrecht, E.,Cooperman, B.S.,Dealwis, C. (登録日: 2008-04-09, 公開日: 2008-08-19, 最終更新日: 2023-11-01)

主引用文献

Xu, H.,Fairman, J.W.,Wijerathna, S.R.,Kreischer, N.R.,LaMacchia, J.,Helmbrecht, E.,Cooperman, B.S.,Dealwis, C.
The Structural Basis for Peptidomimetic Inhibition of Eukaryotic Ribonucleotide Reductase: A Conformationally Flexible Pharmacophore
J.Med.Chem., 51:4653-4659, 2008

PubMed Abstract: Eukaryotic ribonucleotide reductase (RR) catalyzes nucleoside diphosphate conversion to deoxynucleoside diphosphate. Crucial for rapidly dividing cells, RR is a target for cancer therapy. RR activity requires formation of a complex between subunits R1 and R2 in which the R2 C-terminal peptide binds to R1. Here we report crystal structures of heterocomplexes containing mammalian R2 C-terminal heptapeptide, P7 (Ac-1FTLDADF7) and its peptidomimetic P6 (1Fmoc(Me)PhgLDChaDF7) bound to Saccharomyces cerevisiae R1 (ScR1). P7 and P6, both of which inhibit ScRR, each bind at two contiguous sites containing residues that are highly conserved among eukaryotes. Such binding is quite distinct from that reported for prokaryotes. The Fmoc group in P6 peptide makes several hydrophobic interactions that contribute to its enhanced potency in binding to ScR1. Combining all of our results, we observe three distinct conformations for peptide binding to ScR1. These structures provide pharmacophores for designing highly potent nonpeptide class I RR inhibitors.

PubMed: 18610997
DOI: 10.1021/jm800350u

実験手法

X-RAY DIFFRACTION (2.59 Å)