1MRS

CRYSTAL STRUCTURE OF MYCOBACTERIUM TUBERCULOSIS THYMIDYLATE KINASE COMPLEXED WITH 5-CH2OH DEOXYURIDINE MONOPHOSPHATE

1MRS の概要

• エントリーDOI: 10.2210/pdb1mrs/pdb
• 関連するPDBエントリー: 1G3U 1MRN
• 分子名称: THYMIDYLATE KINASE, SULFATE ION, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: transferase (atp:tmp phosphotransferase), kinase, transferase
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 23217.16

構造登録者

Haouz, A.,Vanheusden, V.,Munier-Lehmann, H.,Froeyen, M.,Herdewijn, P.,Van Calenbergh, S.,Delarue, M. (登録日: 2002-09-18, 公開日: 2003-01-07, 最終更新日: 2024-02-14)

主引用文献

Haouz, A.,Vanheusden, V.,Munier-Lehmann, H.,Froeyen, M.
Enzymatic and structural analysis of inhibitors designed against Mycobacterium tuberculosis thymidylate kinase. New insights into the phosphoryl transfer mechanism.
J.Biol.Chem., 278:4963-4971, 2003

PubMed Abstract: The chemical synthesis of new compounds designed as inhibitors of Mycobacterium tuberculosis TMP kinase (TMPK) is reported. The synthesis concerns TMP analogues modified at the 5-position of the thymine ring as well as a novel compound with a six-membered sugar ring. The binding properties of the analogues are compared with the known inhibitor azido-TMP, which is postulated here to work by excluding the TMP-bound Mg(2+) ion. The crystallographic structure of the complex of one of the compounds, 5-CH(2)OH-dUMP, with TMPK has been determined at 2.0 A. It reveals a major conformation for the hydroxyl group in contact with a water molecule and a minor conformation pointing toward Ser(99). Looking for a role for Ser(99), we have identified an unusual catalytic triad, or a proton wire, made of strictly conserved residues (including Glu(6), Ser(99), Arg(95), and Asp(9)) that probably serves to protonate the transferred PO(3) group. The crystallographic structure of the commercially available bisubstrate analogue P(1)-(adenosine-5')-P(5)-(thymidine-5')-pentaphosphate bound to TMPK is also reported at 2.45 A and reveals an alternative binding pocket for the adenine moiety of the molecule compared with what is observed either in the Escherichia coli or in the yeast enzyme structures. This alternative binding pocket opens a way for the design of a new family of specific inhibitors.

PubMed: 12454011
DOI: 10.1074/jbc.M209630200

実験手法

X-RAY DIFFRACTION (2 Å)