9EOT
Structure of human ceramide synthase 6 (CerS6) bound to C16:0 (nanobody Nb02)
Summary for 9EOT
| Entry DOI | 10.2210/pdb9eot/pdb |
| EMDB information | 19869 |
| Descriptor | Isoform 2 of Ceramide synthase 6, Nanobody-02, PALMITIC ACID, ... (5 entities in total) |
| Functional Keywords | ceramide, sphingolipid, covalent intermediate, membrane protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 117040.98 |
| Authors | Pascoa, T.C.,Pike, A.C.W.,Chi, G.,Stefanic, S.,Quigley, A.,Chalk, R.,Mukhopadhyay, S.M.M.,Venkaya, S.,Dix, C.,Moreira, T.,Tessitore, A.,Cole, V.,Chu, A.,Elkins, J.M.,Pautsch, A.,Schnapp, G.,Carpenter, E.P.,Sauer, D.B. (deposition date: 2024-03-15, release date: 2024-11-13, Last modification date: 2025-03-26) |
| Primary citation | Pascoa, T.C.,Pike, A.C.W.,Tautermann, C.S.,Chi, G.,Traub, M.,Quigley, A.,Chalk, R.,Stefanic, S.,Thamm, S.,Pautsch, A.,Carpenter, E.P.,Schnapp, G.,Sauer, D.B. Structural basis of the mechanism and inhibition of a human ceramide synthase. Nat.Struct.Mol.Biol., 32:431-440, 2025 Cited by PubMed Abstract: Ceramides are bioactive sphingolipids crucial for regulating cellular metabolism. Ceramides and dihydroceramides are synthesized by six ceramide synthase (CerS) enzymes, each with specificity for different acyl-CoA substrates. Ceramide with a 16-carbon acyl chain (C16 ceramide) has been implicated in obesity, insulin resistance and liver disease and the C16 ceramide-synthesizing CerS6 is regarded as an attractive drug target for obesity-associated disease. Despite their importance, the molecular mechanism underlying ceramide synthesis by CerS enzymes remains poorly understood. Here we report cryo-electron microscopy structures of human CerS6, capturing covalent intermediate and product-bound states. These structures, along with biochemical characterization, reveal that CerS catalysis proceeds through a ping-pong reaction mechanism involving a covalent acyl-enzyme intermediate. Notably, the product-bound structure was obtained upon reaction with the mycotoxin fumonisin B1, yielding insights into its inhibition of CerS. These results provide a framework for understanding CerS function, selectivity and inhibition and open routes for future drug discovery. PubMed: 39528795DOI: 10.1038/s41594-024-01414-3 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.02 Å) |
Structure validation
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