1uou

From Proteopedia

Revision as of 15:55, 18 December 2007

CRYSTAL STRUCTURE OF HUMAN THYMIDINE PHOSPHORYLASE IN COMPLEX WITH A SMALL MOLECULE INHIBITOR

Overview

Human thymidine phosphorylase (HTP), also known as platelet-derived, endothelial cell growth factor (PD-ECGF), is overexpressed in certain, solid tumors where it is linked to poor prognosis. HTP expression is, utilized for certain chemotherapeutic strategies and is also thought to, play a role in tumor angiogenesis. We determined the structure of HTP, bound to the small molecule inhibitor 5-chloro-6-[1-(2-iminopyrrolidinyl), methyl] uracil hydrochloride (TPI). The inhibitor appears to mimic the, substrate transition state, which may help explain the potency of this, inhibitor and the catalytic mechanism of pyrimidine nucleotide, phosphorylases (PYNPs). Further, we have confirmed the validity of the HTP, structure as a template for structure-based drug design by predicting, binding affinities for TPI and other known HTP inhibitors using in silico, docking techniques. This work provides the first structural insight into, the binding mode of any inhibitor to this important drug target and forms, the basis for designing novel inhibitors for use in anticancer therapy.

Disease

Known disease associated with this structure: Mitochondrial neurogastrointestinal encephalomyopathy syndrome OMIM:[131222]

About this Structure

1UOU is a Single protein structure of sequence from Homo sapiens with CMU as ligand. Active as Thymidine phosphorylase, with EC number 2.4.2.4 Known structural/functional Site: . Full crystallographic information is available from OCA.

Reference

Crystal structure of human thymidine phosphorylase in complex with a small molecule inhibitor., Norman RA, Barry ST, Bate M, Breed J, Colls JG, Ernill RJ, Luke RW, Minshull CA, McAlister MS, McCall EJ, McMiken HH, Paterson DS, Timms D, Tucker JA, Pauptit RA, Structure. 2004 Jan;12(1):75-84. PMID:14725767

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