8QZ7

Structure of human ceramide synthase 6 (CerS6) in complex with N-palmitoyl fumonisin B1

Summary for 8QZ7

• Entry DOI: 10.2210/pdb8qz7/pdb
• EMDB information: 18771
• Descriptor: Isoform 2 of Ceramide synthase 6, Nanobody-22, (2~{R})-2-[2-[(5~{R},6~{R},7~{S},9~{S},11~{R},16~{R},18~{S},19~{S})-6-[(3~{R})-3-carboxy-5-oxidanyl-5-oxidanylidene-pentanoyl]oxy-19-(hexadecanoylamino)-5,9-dimethyl-11,16,18-tris(oxidanyl)icosan-7-yl]oxy-2-oxidanylidene-ethyl]butanedioic acid, ... (5 entities in total)
• Functional Keywords: ceramide, sphingolipid, mycotoxin, fumonisin b1, inhibitory product, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 118921.19

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: 2023-10-26, 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

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: 39528795
DOI: 10.1038/s41594-024-01414-3

Experimental method

ELECTRON MICROSCOPY (3 Å)