期刊
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
卷 81, 期 5, 页码 819-829出版社
WILEY
DOI: 10.1002/prot.24238
关键词
hyperthermophile; phosphoserine phosphatase; HAD family; CAP module; ligand binding
资金
- Marine and Extreme Genome Research Center program (from the Ministry of Land, Transport and Maritime Affairs, Republic of Korea)
- Mid-career Researcher Program (through the National Research Foundation (NRF) in the Ministry of Education, Science and Technology) [2011-0017040/2010-0011602]
Phosphoserine phosphatase (PSP) catalyzes the final and irreversible step of L-serine synthesis by hydrolyzing phosphoserine to produce L-serine and inorganic phosphate. Developing a therapeutic drug that interferes with serine production is of great interest to regulate the pathogenicity of some bacteria and control D-serine levels in neurological diseases. We determined the crystal structure of PSP from the hyperthermophilic archaeon Thermococcus onnurineus at 1.8 angstrom resolution, revealing an NDSB ligand bound to a novel site that is located in a fissure between the catalytic domain and the CAP module. The structure shows a half-open conformation of the CAP 1 module with a unique protruding loop of residues 150155 that possesses a helical conformation in other structures of homologous PSPs. Activity assays indicate that the enzyme exhibits marginal PSP activity at low temperature but a sharp increase in the kcat/KM value, approximately 22 fold, when the temperature is increased. Structural and biochemical analyses suggest that the protruding loop in the active site might be an essential component for the regulation of the activity of PSP from hyperthermophilic T. onnurineus. Identification of this novel binding site distantly located from the catalytic site may be exploited for the development of effective therapeutic allosteric inhibitors against PSP activity. (c) Proteins 2013. (c) 2012 Wiley Periodicals, Inc.
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