title: Structure and mechanism of homoserine kinase: prototype for the GHMP kinase superfamily.
abstract: BACKGROUND
  Homoserine kinase (HSK) catalyzes an important step in the threonine biosynthesis pathway. It belongs to a large yet unique class of small metabolite kinases, the GHMP kinase superfamily. Members in the GHMP superfamily participate in several essential metabolic pathways, such as amino acid biosynthesis, galactose metabolism, and the mevalonate pathway.
  
  
  RESULTS
  The crystal structure of HSK and its complex with ADP reveal a novel nucleotide binding fold. The N-terminal domain contains an unusual left-handed betaalphabeta unit, while the C-terminal domain has a central alpha-beta plait fold with an insertion of four helices. The phosphate binding loop in HSK is distinct from the classical P loops found in many ATP/GTP binding proteins. The bound ADP molecule adopts a rare syn conformation and is in the opposite orientation from those bound to the P loop-containing proteins. Inspection of the substrate binding cavity indicates several amino acid residues that are likely to be involved in substrate binding and catalysis.
  
  
  CONCLUSIONS
  The crystal structure of HSK is the first representative in the GHMP superfamily to have determined structure. It provides insight into the structure and nucleotide binding mechanism of not only the HSK family but also a variety of enzymes in the GHMP superfamily. Such enzymes include galactokinases, mevalonate kinases, phosphomevalonate kinases, mevalonate pyrophosphate decarboxylases, and several proteins of yet unknown functions.
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas 75390, USA.
authors.forename: T
authors.initials: T
authors.lastname: Zhou
authors.forename: M
authors.initials: M
authors.lastname: Daugherty
authors.forename: N V
authors.initials: NV
authors.lastname: Grishin
authors.forename: A L
authors.initials: AL
authors.lastname: Osterman
authors.forename: H
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D002384:Catalysis; D018360:Crystallography, X-Ray; D019281:Dimerization; D005686:Galactokinase / Q000737:chemistry / Q000378:metabolism; D006593:Hexokinase / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D017017:Methanococcus / Q000201:enzymology*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D010446:Peptide Fragments; D000244:Adenosine Diphosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); D006593:Hexokinase; C022534:ribokinase; C021796:mevalonate kinase; C021370:homoserine kinase; D005686:Galactokinase