Structures of 5-methylthioribose kinase reveal substrate specificity and unusual mode of nucleotide binding

Shao Yang Ku, Patrick Yip, Kenneth A. Cornell, Michael Riscoe, Jean Bernard Behr, Georges Guillerm, P. Lynne Howell

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

The methionine salvage pathway is ubiquitous in all organisms, but metabolic variations exist between bacteria and mammals. 5-Methylthioribose (MTR) kinase is a key enzyme in methionine salvage in bacteria and the absence of a mammalian homolog suggests that it is a good target for the design of novel antibiotics. The structures of the apo-form of Bacillus subtilis MTR kinase, as well as its ADP, ADP-PO4, AMPPCP, and AMPPCP-MTR complexes have been determined. MTR kinase has a bilobal eukaryotic protein kinase fold but exhibits a number of unique features. The protein lacks the DFG motif typically found at the beginning of the activation loop and instead coordinates magnesium via a DXE motif (Asp250-Glu252). In addition, the glycine-rich loop of the protein, analogous to the "Gly triad" in protein kinases, does not interact extensively with the nucleotide. The MTR substrate-binding site consists of Asp233 of the catalytic HGD motif, a novel twin arginine motif (Arg340/Arg341), and a semi-conserved W-loop, which appears to regulate MTR binding specificity. No lobe closure is observed for MTR kinase upon substrate binding. This is probably because the enzyme lacks the lobe closure/inducing interactions between the C-lobe of the protein and the ribosyl moiety of the nucleotide that are typically responsible for lobe closure in protein kinases. The current structures suggest that MTR kinase has a dissociative mechanism.

Original languageEnglish (US)
Pages (from-to)22195-22206
Number of pages12
JournalJournal of Biological Chemistry
Volume282
Issue number30
DOIs
StatePublished - Jul 27 2007
Externally publishedYes

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Substrate Specificity
Protein Kinases
Salvaging
Phosphotransferases
Nucleotides
Methionine
ATP Synthetase Complexes
Bacteria
Substrates
Adenosine Diphosphate
Proteins
Mammals
Bacilli
Enzymes
Glycine
Magnesium
Arginine
Protein C
Bacillus subtilis
Chemical activation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Structures of 5-methylthioribose kinase reveal substrate specificity and unusual mode of nucleotide binding. / Ku, Shao Yang; Yip, Patrick; Cornell, Kenneth A.; Riscoe, Michael; Behr, Jean Bernard; Guillerm, Georges; Howell, P. Lynne.

In: Journal of Biological Chemistry, Vol. 282, No. 30, 27.07.2007, p. 22195-22206.

Research output: Contribution to journalArticle

Ku, Shao Yang ; Yip, Patrick ; Cornell, Kenneth A. ; Riscoe, Michael ; Behr, Jean Bernard ; Guillerm, Georges ; Howell, P. Lynne. / Structures of 5-methylthioribose kinase reveal substrate specificity and unusual mode of nucleotide binding. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 30. pp. 22195-22206.
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