GTP preference of d-glycero-α-d-manno-heptose-1-phosphate guanylyltransferase from yersinia pseudotuberculosis

Suwon Kim, Mi Sun Kim, Seri Jo, Dong Hae Shin

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D-glycero-α-d-manno-heptose-1-phosphate guanylyltransferase (HddC) is the fourth enzyme synthesizing a building component of lipopolysaccharide (LPS) of Gram-negative bacteria. Since HddC is a potential new target to develop antibiotics, the analysis of the structural and functional relationship of the complex structure will lead to a better idea to design inhibitory compounds. X-ray crystallography and biochemical experiments to elucidate the guanine preference were performed based on the multiple sequence alignment. The crystal structure of HddC from Yersinia pseudotuberculosis (YPT) complexed with guanosine 5-(β-amino)-diphosphate (GMPPN) has been determined at 1.55 Å resolution. Meanwhile, the mutants revealed their reduced guanine affinity, instead of acquiring noticeable pyrimidine affinity. The complex crystal structure revealed that GMPPN is docked in the catalytic site with the aid of Glu80 positioning on the conserved motif EXXPLGTGGA. In the HddC family, this motif is expected to recruit nucleotides through interacting with bases. The crystal structure shows that oxygen atoms of Glu80 forming two hydrogen bonds play a critical role in interaction with two nitrogen atoms of the guanine base of GMPPN. Interestingly, the binding of GMPPN induced the formation of an oxyanion hole-like conformation on the L(S/A/G)X(S/G) motif and consequently influenced on inducing a conformational shift of the region around Ser55.

Original languageEnglish
Article number280
JournalInternational Journal of Molecular Sciences
Issue number1
StatePublished - 1 Jan 2020

Bibliographical note

Funding Information:
Funding: This work was supported by funded by the National Research Foundation of Korea (NFR), the Basic Science Research Programs, 2018R1D1A1B07050781 to DHS and 2018R1D1A1B07050942 to M.-S.K., granted by the Ministry of Education, Science and Technology, Republic of Korea (MEST).

Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.


  • Antibiotics
  • D-glycero-α-d-manno-heptose-1-phosphate guanylyltransferase (HddC)
  • Guanine specificity
  • Guanosine-5-(β-amino)-diphosphate (GMPPN)
  • Yersinia pseudotuberculosis (YPT)


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