4p5e

From Proteopedia

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

PDB ID 4p5e

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Structural highlights

4p5e is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.35Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

DNPH1_HUMAN Catalyzes the cleavage of the N-glycosidic bond of deoxyribonucleoside 5'-monophosphates to yield deoxyribose 5-phosphate and a purine or pyrimidine base. Deoxyribonucleoside 5'-monophosphates containing purine bases are preferred to those containing pyrimidine bases (By similarity).[HAMAP-Rule:MF_03036]

Publication Abstract from PubMed

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.

6-(Hetero)Arylpurine nucleotides as inhibitors of the oncogenic target DNPH1: Synthesis, structural studies and cytotoxic activities.,Amiable C, Paoletti J, Haouz A, Padilla A, Labesse G, Kaminski PA, Pochet S Eur J Med Chem. 2014 Aug 1;85C:418-437. doi: 10.1016/j.ejmech.2014.07.110. PMID:25108359^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Amiable C, Paoletti J, Haouz A, Padilla A, Labesse G, Kaminski PA, Pochet S. 6-(Hetero)Arylpurine nucleotides as inhibitors of the oncogenic target DNPH1: Synthesis, structural studies and cytotoxic activities. Eur J Med Chem. 2014 Aug 1;85C:418-437. doi: 10.1016/j.ejmech.2014.07.110. PMID:25108359 doi:http://dx.doi.org/10.1016/j.ejmech.2014.07.110