4WGK
Crystal structure of human neutral ceramidase with Zn-bound phosphate
Summary for 4WGK
| Entry DOI | 10.2210/pdb4wgk/pdb |
| Descriptor | Neutral ceramidase, 1,2-ETHANEDIOL, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (11 entities in total) |
| Functional Keywords | ceramidase, amidase, zinc, phosphate, hydrolase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 155831.60 |
| Authors | Airola, M.V.,Pulkoski-Gross, M.J.,Obeid, L.M.,Hannun, Y.A. (deposition date: 2014-09-18, release date: 2015-07-08, Last modification date: 2024-11-06) |
| Primary citation | Airola, M.V.,Allen, W.J.,Pulkoski-Gross, M.J.,Obeid, L.M.,Rizzo, R.C.,Hannun, Y.A. Structural Basis for Ceramide Recognition and Hydrolysis by Human Neutral Ceramidase. Structure, 23:1482-1491, 2015 Cited by PubMed Abstract: 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-Å crystal structure of human nCDase in complex with phosphate that reveals a striking, 20-Å 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 Zn(2+)-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. PubMed: 26190575DOI: 10.1016/j.str.2015.06.013 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.582 Å) |
Structure validation
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