GTP Preference of D-Glycero-alpha-D-manno-Heptose-1-Phosphate Guanylyltransferase from Yersinia pseudotuberculosis
- 주제(키워드) D-glycero-alpha-D-manno-heptose-1-phosphate guanylyltransferase (HddC) , Yersinia pseudotuberculosis (YPT) , guanosine-5 '-(beta-amino)-diphosphate (GMPPN) , guanine specificity , antibiotics
- 주제(기타) Biochemistry & Molecular Biology
- 주제(기타) Chemistry, Multidisciplinary
- 설명문(일반) [Kim, Suwon; Kim, Mi-Sun; Jo, Seri; Shin, Dong Hae] Ewha Womans Univ, Grad Sch Pharmaceut Sci, 52 Ewhayeodae Gil, Seoul 03760, South Korea
- 등재 SCIE, SCOPUS
- OA유형 gold, Green Published
- 발행기관 MDPI
- 발행년도 2020
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000171951
- 본문언어 영어
- Published As https://dx.doi.org/10.3390/ijms21010280
- PubMed https://pubmed.ncbi.nlm.nih.gov/31906195
초록/요약
D-glycero-alpha-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 '-(beta-amino)-diphosphate (GMPPN) has been determined at 1.55 angstrom 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.
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