1H7E

The Structure of Cmp:2-Keto-3-Deoxy-Manno-Octonic Acid Synthetase and of its Complexes with Substrates and Substrate Analogs

(2001) J Mol Biol 312: 143

• PubMed: 11545592 Search on PubMed
• DOI: https://doi.org/10.1006/jmbi.2001.4948
• Primary Citation of Related Structures:  
  1H7E, 1H7F, 1H7G, 1H7H, 1H7T


• PubMed 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.

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Organizational Affiliation: 

Institut für Organische Chemie und Biochemie, Albert-Ludwigs-Universit?t, Albertstr. 21, Freiburg im Breisgau, Germany, 79104.