4BQS

Crystal structure of Mycobacterium tuberculosis shikimate kinase in complex with ADP and a shikimic acid derivative.

4BQS の概要

• エントリーDOI: 10.2210/pdb4bqs/pdb
• 分子名称: SHIKIMATE KINASE, ADENOSINE-5'-DIPHOSPHATE, (1R,6R,10S)-6,10-dihydroxy-2-oxabicyclo[4.3.1]deca-4(Z),7-diene-8-carboxylic acid, ... (4 entities in total)
• 機能のキーワード: transferase, phosphotransferases (alcohol group acceptor), shikimic acid pathway, inhibitor
• 由来する生物種: MYCOBACTERIUM TUBERCULOSIS
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 57755.26

構造登録者

Otero, J.M.,Garcia-Doval, C.,Llamas-Saiz, A.L.,Blanco, B.,Prado, V.,Lence, E.,Lamb, H.,Hawkins, A.R.,Gonzalez-Bello, C.,van Raaij, M.J. (登録日: 2013-06-02, 公開日: 2013-08-07, 最終更新日: 2023-12-20)

主引用文献

Blanco, B.,Prado, V.,Lence, E.,Otero, J.M.,Garcia-Doval, C.,van Raaij, M.J.,Llamas-Saiz, A.L.,Lamb, H.,Hawkins, A.R.,Gonzalez-Bello, C.
Mycobacterium tuberculosis shikimate kinase inhibitors: design and simulation studies of the catalytic turnover.
J. Am. Chem. Soc., 135:12366-12376, 2013

PubMed Abstract: Shikimate kinase (SK) is an essential enzyme in several pathogenic bacteria and does not have any counterpart in human cells, thus making it an attractive target for the development of new antibiotics. The key interactions of the substrate and product binding and the enzyme movements that are essential for catalytic turnover of the Mycobacterium tuberculosis shikimate kinase enzyme (Mt-SK) have been investigated by structural and computational studies. Based on these studies several substrate analogs were designed and assayed. The crystal structure of Mt-SK in complex with ADP and one of the most potent inhibitors has been solved at 2.15 Å. These studies reveal that the fixation of the diaxial conformation of the C4 and C5 hydroxyl groups recognized by the enzyme or the replacement of the C3 hydroxyl group in the natural substrate by an amino group is a promising strategy for inhibition because it causes a dramatic reduction of the flexibility of the LID and shikimic acid binding domains. Molecular dynamics simulation studies showed that the product is expelled from the active site by three arginines (Arg117, Arg136, and Arg58). This finding represents a previously unknown key role of these conserved residues. These studies highlight the key role of the shikimic acid binding domain in the catalysis and provide guidance for future inhibitor designs.

PubMed: 23889343
DOI: 10.1021/ja405853p

実験手法

X-RAY DIFFRACTION (2.15 Å)