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Crystallographic studies of shikimate binding and induced conformational changes in Mycobacterium tuberculosis shikimate kinase
Author(s) -
Dhaliwal Balvinder,
Nichols Charles E.,
Ren Jingshan,
Lockyer Michael,
Charles Ian,
Hawkins Alastair R.,
Stammers David K.
Publication year - 2004
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2004.08.005
Subject(s) - shikimate pathway , shikimic acid , chemistry , stereochemistry , mycobacterium tuberculosis , biochemistry , aromatic amino acids , enzyme , tuberculosis , medicine , pathology
The X‐ray crystal structure of Mycobacterium tuberculosis shikimate kinase (SK) with bound shikimate and adenosine diphosphate (ADP) has been determined to a resolution of 2.15 Å. The binding of shikimate in a shikimate kinase crystal structure has not previously been reported. The substrate binds in a pocket lined with hydrophobic residues and interacts with several highly conserved charged residues including Asp34, Arg58, Glu61 and Arg136 which project into the cavity. Comparisons of our ternary SK–ADP–shikimate complex with an earlier binary SK–ADP complex show that conformational changes occur on shikimate binding with the substrate‐binding domain rotating by 10°. Detailed knowledge of shikimate binding is an important step in the design of inhibitors of SK, which have potential as novel anti‐tuberculosis agents.