4P5D

CRYSTAL STRUCTURE OF RAT DNPH1 (RCL) WITH 6-NAPHTHYL-PURINE-RIBOSIDE-MONOPHOSPHATE

4P5D の概要

• エントリーDOI: 10.2210/pdb4p5d/pdb
• 関連するPDBエントリー: 4FYI
• 分子名称: 2'-deoxynucleoside 5'-phosphate N-hydrolase 1, 6-(naphthalen-2-yl)-9-(5-O-phosphono-beta-D-ribofuranosyl)-9H-purine, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: n-glycosidase, inhibitor, hydrolase
• 由来する生物種: Rattus norvegicus (Rat)
• 細胞内の位置: Cytoplasm (By similarity): O35820
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 35359.45

構造登録者

Padilla, A.,Labesse, G.,Kaminski, P.A. (登録日: 2014-03-16, 公開日: 2014-08-20, 最終更新日: 2023-12-20)

主引用文献

Amiable, C.,Paoletti, J.,Haouz, A.,Padilla, A.,Labesse, G.,Kaminski, P.A.,Pochet, S.
6-(Hetero)Arylpurine nucleotides as inhibitors of the oncogenic target DNPH1: Synthesis, structural studies and cytotoxic activities.
Eur.J.Med.Chem., 85C:418-437, 2014

PubMed Abstract: The 2'-deoxynucleoside 5'-phosphate N-hydrolase 1 (DNPH1) has been proposed as a new molecular target for cancer treatment. Here, we describe the synthesis of a series of novel 6-aryl- and 6-heteroarylpurine riboside 5'-monophosphates via Suzuki-Miyaura cross-coupling reactions, and their ability to inhibit recombinant rat and human DNPH1. Enzymatic inhibition studies revealed competitive inhibitors in the low micromolar range. Crystal structures of human and rat DNPH1 in complex with one nucleotide from this series, the 6-naphthylpurine derivative, provided detailed structural information, in particular regarding the possible conformations of a long and flexible loop wrapping around the large hydrophobic substituent. Taking advantage of these high-resolution structures, we performed virtual docking studies in order to evaluate enzyme-inhibitor interactions for the whole compound series. Among the synthesized compounds, several molecules exhibited significant in vitro cytotoxicity against human colon cancer (HCT15, HCT116) and human promyelocytic leukemia (HL60) cell lines with IC50 values in the low micromolar range, which correlated with in vitro DNPH1 inhibitory potency.

PubMed: 25108359
DOI: 10.1016/j.ejmech.2014.07.110

実験手法

X-RAY DIFFRACTION (2.11 Å)