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Title: Crystal Structures of Candida albicans Phosphodiesterase 2 and Implications for Its Biological Functions

Abstract

The cAMP signaling system plays important roles in the physiological processes of pathogen yeast Candida albicans, but its functional mechanism has not been well illustrated. Here, we report the enzymatic characterization and crystal structures of C. albicans phosphodiesterase 2 (caPDE2) in the unliganded and 3-isobutyl-1-methylxanthine-complexed forms. caPDE2 is a monomer in liquid and crystal states and specifically hydrolyzes cAMP with a KM of 35 nM. It does not effectively hydrolyze cGMP as shown by the 1.32 × 105-fold specificity of cAMP/cGMP. The crystal structure of caPDE2 shows significant differences from those of human PDEs. First, the N-terminal fragment of caPDE2 (residues 1–201) tightly associates with the catalytic domain to form a rigid molecular entity, implying its stable molecular conformation for C. albicans to resist environmental stresses. Second, the M-loop, a critical fragment for binding of the substrate and inhibitors to human PDEs, is not a part of the caPDE2 active site. In conclusion, this feature of caPDE2 may provide a structural basis for the design of selective inhibitors for the treatment of yeast infection.

Authors:
 [1];  [2];  [1];  [1];  [1];  [3];  [4];  [1]; ORCiD logo [5]
  1. Beijing Technology and Business Univ. (China)
  2. Univ. of North Carolina, Chapel Hill, NC (United States); Sun Yat-Sen Univ., Guangzhou (China)
  3. Univ. of North Carolina, Chapel Hill, NC (United States); Univ. of Electronic Science and Technology of China, Sichuan (China)
  4. National Inst. of Health, Research Triangle Park, NC (United States)
  5. Univ. of North Carolina, Chapel Hill, NC (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Inst. of Health; National Natural Science Foundation of China (NSFC); National Inst. of Environmental Health Sciences
OSTI Identifier:
1482251
Grant/Contract Number:  
GM59791; 31471626; 31291944
Resource Type:
Accepted Manuscript
Journal Name:
Biochemistry
Additional Journal Information:
Journal Volume: 57; Journal Issue: 42; Journal ID: ISSN 0006-2960
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; palladium; crystal structure; fungi; Inhibitors; conformation; phosphodiesterase; yeast; second messenger cAMP; enzymatic kinetics

Citation Formats

Yao, Ting, Huang, Yiyou, Zhang, Meng, Chen, Yujuan, Pei, Hairun, Shi, Jianyou, Wang, Huanchen, Wang, Yousheng, and Ke, Hengming. Crystal Structures of Candida albicans Phosphodiesterase 2 and Implications for Its Biological Functions. United States: N. p., 2018. Web. https://doi.org/10.1021/acs.biochem.8b00707.
Yao, Ting, Huang, Yiyou, Zhang, Meng, Chen, Yujuan, Pei, Hairun, Shi, Jianyou, Wang, Huanchen, Wang, Yousheng, & Ke, Hengming. Crystal Structures of Candida albicans Phosphodiesterase 2 and Implications for Its Biological Functions. United States. https://doi.org/10.1021/acs.biochem.8b00707
Yao, Ting, Huang, Yiyou, Zhang, Meng, Chen, Yujuan, Pei, Hairun, Shi, Jianyou, Wang, Huanchen, Wang, Yousheng, and Ke, Hengming. Wed . "Crystal Structures of Candida albicans Phosphodiesterase 2 and Implications for Its Biological Functions". United States. https://doi.org/10.1021/acs.biochem.8b00707. https://www.osti.gov/servlets/purl/1482251.
@article{osti_1482251,
title = {Crystal Structures of Candida albicans Phosphodiesterase 2 and Implications for Its Biological Functions},
author = {Yao, Ting and Huang, Yiyou and Zhang, Meng and Chen, Yujuan and Pei, Hairun and Shi, Jianyou and Wang, Huanchen and Wang, Yousheng and Ke, Hengming},
abstractNote = {The cAMP signaling system plays important roles in the physiological processes of pathogen yeast Candida albicans, but its functional mechanism has not been well illustrated. Here, we report the enzymatic characterization and crystal structures of C. albicans phosphodiesterase 2 (caPDE2) in the unliganded and 3-isobutyl-1-methylxanthine-complexed forms. caPDE2 is a monomer in liquid and crystal states and specifically hydrolyzes cAMP with a KM of 35 nM. It does not effectively hydrolyze cGMP as shown by the 1.32 × 105-fold specificity of cAMP/cGMP. The crystal structure of caPDE2 shows significant differences from those of human PDEs. First, the N-terminal fragment of caPDE2 (residues 1–201) tightly associates with the catalytic domain to form a rigid molecular entity, implying its stable molecular conformation for C. albicans to resist environmental stresses. Second, the M-loop, a critical fragment for binding of the substrate and inhibitors to human PDEs, is not a part of the caPDE2 active site. In conclusion, this feature of caPDE2 may provide a structural basis for the design of selective inhibitors for the treatment of yeast infection.},
doi = {10.1021/acs.biochem.8b00707},
journal = {Biochemistry},
number = 42,
volume = 57,
place = {United States},
year = {2018},
month = {9}
}

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