4BQS

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

Summary for 4BQS

• Entry DOI: 10.2210/pdb4bqs/pdb
• Descriptor: 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)
• Functional Keywords: transferase, phosphotransferases (alcohol group acceptor), shikimic acid pathway, inhibitor
• Biological source: MYCOBACTERIUM TUBERCULOSIS
• Total number of polymer chains: 3
• Total formula weight: 57755.26

Authors

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. (deposition date: 2013-06-02, release date: 2013-08-07, Last modification date: 2023-12-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.15 Å)