PMID:11545592
| Citation |
Jelakovic, S and Schulz, GE (2001) The structure of CMP:2-keto-3-deoxy-manno-octonic acid synthetase and of its complexes with substrates and substrate analogs. J. Mol. Biol. 312:143-55 |
|---|---|
| Abstract |
The enzyme CMP-Kdo synthetase (CKS) catalyzes the activation of the sugar Kdo (2-keto-3-deoxy-manno-octonic acid) by forming a monophosphate diester. CKS is a pharmaceutical target because CMP-Kdo is used in the biosynthesis of lipopolysaccharides that are vital for Gram-negative bacteria. We have refined the structure of the unligated capsule-specific CKS from Escherichia coli at 1.8 A resolution (1 A=0.1 nm) and we have established the structures of its complexes with the substrate CTP, with CDP and CMP as well as with the product analog CMP-NeuAc (CMP-sialate) by X-ray diffraction analyses at resolutions between 2.1 A and 2.5 A. The N-terminal domains of the dimeric enzyme bind CTP in a peculiar nucleotide-binding fold, whereas the C-terminal domains form the dimer interface. The observed binding geometries together with the amino acid variabilities during evolution and the locations of a putative Mg(2+) and of a very strongly bound water molecule suggest a pathway for the catalysis. The N-terminal domain shows sequence homology with the CMP-NeuAc synthetases. Moreover, the chain fold and the substrate-binding position of CKS resemble those of other enzymes processing nucleotide-sugars. |
| Links |
PubMed Online version:10.1006/jmbi.2001.4948 |
| Keywords |
Amino Acid Sequence; Conserved Sequence; Crystallography, X-Ray; Cytidine Diphosphate/chemistry; Cytidine Diphosphate/metabolism; Cytidine Monophosphate/chemistry; Cytidine Monophosphate/metabolism; Cytidine Monophosphate N-Acetylneuraminic Acid/chemistry; Cytidine Monophosphate N-Acetylneuraminic Acid/metabolism; Cytidine Triphosphate/chemistry; Cytidine Triphosphate/metabolism; Dimerization; Escherichia coli/enzymology; Models, Molecular; Molecular Sequence Data; N-Acylneuraminate Cytidylyltransferase/chemistry; Nucleotidyltransferases/chemistry; Nucleotidyltransferases/metabolism; Protein Conformation; Protein Folding; Sequence Homology, Amino Acid |
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