title: Crystallographic studies of shikimate binding and induced conformational changes in Mycobacterium tuberculosis shikimate kinase.
abstract: 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.
authors.affiliation: Division of Structural Biology, The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
authors.forename: Balvinder
authors.initials: B
authors.lastname: Dhaliwal
authors.forename: Charles E
authors.initials: CE
authors.lastname: Nichols
authors.forename: Jingshan
authors.initials: J
authors.lastname: Ren
authors.forename: Michael
authors.initials: M
authors.lastname: Lockyer
authors.forename: Ian
authors.initials: I
authors.lastname: Charles
authors.forename: Alastair R
authors.initials: AR
authors.lastname: Hawkins
authors.forename: David K
authors.initials: DK
authors.lastname: Stammers
mesh_terms: 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
chemical_list: D012765:Shikimic Acid; D017853:Phosphotransferases (Alcohol Group Acceptor); C022642:shikimate kinase