title: Structures of 5-methylthioribose kinase reveal substrate specificity and unusual mode of nucleotide binding.
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-PO(4), 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 (Asp(250)-Glu(252)). 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 Asp(233) of the catalytic HGD motif, a novel twin arginine motif (Arg(340)/Arg(341)), 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.
authors.affiliation: Program in Molecular Structure and Function, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Shao-Yang
authors.initials: SY
authors.lastname: Ku
authors.forename: Patrick
authors.initials: P
authors.lastname: Yip
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Cornell
authors.forename: Michael K
authors.initials: MK
authors.lastname: Riscoe
authors.forename: Jean-Bernard
authors.initials: JB
authors.lastname: Behr
authors.forename: Georges
authors.initials: G
authors.lastname: Guillerm
authors.forename: P Lynne
authors.initials: PL
authors.lastname: Howell
mesh_terms: D000227:Adenine Nucleotides / Q000378:metabolism*; D001412:Bacillus subtilis / Q000201:enzymology*; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D008715:Methionine / Q000378:metabolism; D008958:Models, Molecular; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D017510:Protein Folding; D012266:Ribose / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000227:Adenine Nucleotides; D001426:Bacterial Proteins; D012266:Ribose; D008715:Methionine; D017853:Phosphotransferases (Alcohol Group Acceptor); C021787:5-methylthioribose kinase