EMD-19869
Structure of human ceramide synthase 6 (CerS6) bound to C16:0 (nanobody Nb02)
EMD-19869
Single-particle3.02 Å
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Map released: 13/11/2024
Last modified: 27/11/2024
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
Sample: CerS6-Nb02 complex
Fitted models: 9eot (Avg. Q-score: 0.487)
Deposition Authors: Pascoa TC
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Structural basis of the mechanism and inhibition of a human ceramide synthase.
Pascoa TC
,
Pike ACW
,
Tautermann CS
,
Chi G
,
Traub M,
Quigley A
,
Chalk R,
Stefanic S
,
Thamm S
,
Pautsch A
,
Carpenter EP
,
Schnapp G
,
Sauer DB
(2024) Nat Struct Mol Biol
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(2024) Nat Struct Mol Biol
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.
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.