2J0F

Structural basis for non-competitive product inhibition in human thymidine phosphorylase: implication for drug design

2J0F の概要

• エントリーDOI: 10.2210/pdb2j0f/pdb
• 関連するPDBエントリー: 1UOU
• 分子名称: THYMIDINE PHOSPHORYLASE, THYMINE (3 entities in total)
• 機能のキーワード: htp, chemotaxis, transferase, polymorphism, disease mutation, glycosyltransferase, angiogenesis, growth factor, differentiation, developmental protein, human thymidine phosphorylase
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 200499.86

構造登録者

El Omari, K.,Bronckaers, A.,Liekens, S.,Perez-Perez, M.J.,Balzarini, J.,Stammers, D.K. (登録日: 2006-08-02, 公開日: 2006-10-11, 最終更新日: 2023-12-13)

主引用文献

El Omari, K.,Bronckaers, A.,Liekens, S.,Perez-Perez, M.,Balzarini, J.,Stammers, D.K.
Structural Basis for Non-Competitive Product Inhibition in Human Thymidine Phosphorylase: Implications for Drug Design.
Biochem.J., 399:199-, 2006

PubMed Abstract: HTP (human thymidine phosphorylase), also known as PD-ECGF (platelet-derived endothelial cell growth factor) or gliostatin, has an important role in nucleoside metabolism. HTP is implicated in angiogenesis and apoptosis and therefore is a prime target for drug design, including antitumour therapies. An HTP structure in a closed conformation complexed with an inhibitor has previously been solved. Earlier kinetic studies revealed an ordered release of thymine followed by ribose phosphate and product inhibition by both ligands. We have determined the structure of HTP from crystals grown in the presence of thymidine, which, surprisingly, resulted in bound thymine with HTP in a closed dead-end complex. Thus thymine appears to be able to reassociate with HTP after its initial ordered release before ribose phosphate and induces the closed conformation, hence explaining the mechanism of non-competitive product inhibition. In the active site in one of the four HTP molecules within the crystal asymmetric unit, additional electron density is present. This density has not been previously seen in any pyrimidine nucleoside phosphorylase and it defines a subsite that may be exploitable in drug design. Finally, because our crystals did not require proteolysed HTP to grow, the structure reveals a loop (residues 406-415), disordered in the previous HTP structure. This loop extends across the active-site cleft and appears to stabilize the dimer interface and the closed conformation by hydrogen-bonding. The present study will assist in the design of HTP inhibitors that could lead to drugs for anti-angiogenesis as well as for the potentiation of other nucleoside drugs.

PubMed: 16803458
DOI: 10.1042/BJ20060513

実験手法

X-RAY DIFFRACTION (2.31 Å)