Crystallographic studies of shikimate binding and induced conformational changes in Mycobacterium tuberculosis shikimate kinase.
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 A. 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 degrees. Detailed knowledge of shikimate binding is an important step in the design of inhibitors of SK, which have potential as novel anti-tuberculosis agents.
Dhaliwal
Balvinder
B
Division of Structural Biology, The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Nichols
Charles E
CE
Ren
Jingshan
J
Lockyer
Michael
M
Charles
Ian
I
Hawkins
Alastair R
AR
Stammers
David K
DK
D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D012765:Shikimic Acid / Q000378:metabolism*; D013379:Substrate Specificity
D012765:Shikimic Acid; D017853:Phosphotransferases (Alcohol Group Acceptor); C022642:shikimate kinase