期刊
STRUCTURE
卷 23, 期 8, 页码 1482-1491出版社
CELL PRESS
DOI: 10.1016/j.str.2015.06.013
关键词
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资金
- NIH grants [R01CA172517, F32GM100679, R01GM097741, T32GM007518]
- MERIT Award from the US Department of Veterans Affairs [BX000156]
- ONO Pharmaceuticals
- SBU Office of the Vice President for Research
Neutral ceramidase (nCDase) catalyzes conversion of the apoptosis-associated lipid ceramide to sphingosine, the precursor for the proliferative factor sphingosine-1-phosphate. As an enzyme regulating the balance of ceramide and sphingosine-1-phosphate, nCDase is emerging as a therapeutic target for cancer. Here, we present the 2.6-angstrom crystal structure of human nCDase in complex with phosphate that reveals a striking, 20-angstrom deep, hydrophobic active site pocket stabilized by a eukaryotic-specific subdomain not present in bacterial ceramidases. Utilizing flexible ligand docking, we predict a likely binding mode for ceramide that superimposes closely with the crystallographically observed transition state analog phosphate. Our results suggest that nCDase uses a new catalytic strategy for Zn2+-dependent amidases, and generates ceramide specificity by sterically excluding sphingolipids with bulky headgroups and specifically recognizing the small hydroxyl head group of ceramide. Together, these data provide a foundation to aid drug development and establish common themes for how proteins recognize the bioactive lipid ceramide.
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