1NN0

Crystal structure of human thymidylate kinase with ddTMP and ADP

1NN0 の概要

• エントリーDOI: 10.2210/pdb1nn0/pdb
• 分子名称: Thymidylate kinase, MAGNESIUM ION, 3'-DEOXYTHYMIDINE-5'-MONOPHOSPHATE, ... (5 entities in total)
• 機能のキーワード: thymidylate kinase, p-loop, dideoxythymidine, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 24834.55

構造登録者

Ostermann, N.,Segura-Pena, D.,Meier, C.,Veit, T.,Monnerjahn, M.,Konrad, M.,Lavie, A. (登録日: 2003-01-12, 公開日: 2003-03-18, 最終更新日: 2024-02-14)

主引用文献

Ostermann, N.,Segura-Pena, D.,Meier, C.,Veit, T.,Monnerjahn, M.,Konrad, M.,Lavie, A.
Structures of human thymidylate kinase in complex with prodrugs: implications for the structure-based design of novel compounds
Biochemistry, 42:2568-2577, 2003

PubMed Abstract: Nucleoside analogue prodrugs are dependent on efficient intracellular stepwise phosphorylation to their triphosphate form to become therapeutically active. In many cases it is this activation pathway that largely determines the efficacy of the drug. To gain further understanding of the determinants for efficient conversion by the enzyme thymidylate kinase (TMPK) of clinically important thymidine monophosphate analogues to the corresponding diphosphates, we solved the crystal structures of the enzyme, with either ADP or the ATP analogue AppNHp at the phosphoryl donor site, in complex with TMP, AZTMP (previous work), NH2TMP, d4TMP, ddTMP, and FLTMP (this work) at the phosphoryl acceptor site. In conjunction with steady-state kinetic data, our structures shed light on the effect of 3'-substitutions in the nucleoside monophosphate (NMP) sugar moiety on the catalytic rate. We observe a direct correlation between the rate of phosphorylation of an NMP and its ability to induce a closing of the enzyme's phosphate-binding loop (P-loop). Our results show the drastic effects that slight modifications of the substrates exert on the enzyme's conformation and, hence, activity and suggest the type of substitutions that are compatible with efficient phosphorylation by TMPK.

PubMed: 12614151
DOI: 10.1021/bi027302t

実験手法

X-RAY DIFFRACTION (1.6 Å)