EMD-19869

Single-particle
3.02 Å
EMD-19869 Deposition: 15/03/2024
Map released: 13/11/2024
Last modified: 27/11/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-19869

Structure of human ceramide synthase 6 (CerS6) bound to C16:0 (nanobody Nb02)

EMD-19869

Single-particle
3.02 Å
EMD-19869 Deposition: 15/03/2024
Map released: 13/11/2024
Last modified: 27/11/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Homo sapiens, Vicugna pacos
Sample: CerS6-Nb02 complex
Fitted models: 9eot (Avg. Q-score: 0.487)

Deposition Authors: Pascoa TC , Pike ACW , Chi G , Stefanic S , Quigley A , Chalk R, Mukhopadhyay SMM, Venkaya S, Dix C, Moreira T, Tessitore A, Cole V, Chu A, Elkins JM, Pautsch A , Schnapp G , Carpenter EP , Sauer DB
Structural basis of the mechanism and inhibition of a human ceramide synthase.
PUBMED: 39528795
DOI: doi:10.1038/s41594-024-01414-3
ISSN: 1545-9985
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.