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J. Biol. Chem., Vol. 277, Issue 6, 4343-4350, February 8, 2002

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Structure and Mechanism of CTP:Phosphocholine Cytidylyltransferase (LicC) from Streptococcus pneumoniae^*

Bo-Yeon Kwak, Yong-Mei Zhang^§, Mikyung Yun, Richard J. Heath^§, Charles O. Rock^§¶, Suzanne Jackowski^§¶, and Hee-Won Park^¶

From the  Department of Structural Biology and the ^§ Protein Science Division, Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105 and the ^¶ Department of Molecular Biosciences, University of Tennessee Health Science Center, Memphis, Tennessee 38163

Pneumococcal LicC is a member of the nucleoside triphosphate transferase superfamily and catalyzes the transfer of a cytidine monophosphate from CTP to phosphocholine to form CDP-choline. The structures of apo-LicC and the LicC·CDP-choline·Mg²⁺ ternary complex were determined, and the comparison of these structures reveals a significant conformational change driven by the multivalent coordination of Mg²⁺. The key event is breaking the Glu²¹⁶·Arg¹²⁹ salt bridge, which triggers the coalescence of four individual -strands into two extended -sheets. These movements reorient the side chains of Trp¹³⁶ and Tyr¹⁹⁰ for the optimal binding and alignment of the phosphocholine moiety. Consistent with these conformational changes, LicC operates via a compulsory ordered kinetic mechanism. The structures explain the substrate specificity of LicC for CTP and phosphocholine and implicate a direct role for Mg²⁺ in aligning phosphocholine for in-line nucleophilic attack and stabilizing the negative charge that develops in the pentacoordinate transition state. These results provide a structural basis for assigning a specific role for magnesium in the catalytic mechanism of pneumococcal LicC.

The atomic coordinates and the structure factors (code 1jyk and 1jyl) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

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