8Y2N

Cryo-EM structure of the apo Lac1-Lip1 complex

Summary for 8Y2N

• Entry DOI: 10.2210/pdb8y2n/pdb
• EMDB information: 38857 38858
• Descriptor: Ceramide synthase LAC1, Ceramide synthase subunit LIP1, (4S,7R)-4-HYDROXY-N,N,N-TRIMETHYL-9-OXO-7-[(PALMITOYLOXY)METHYL]-3,5,8-TRIOXA-4-PHOSPHAHEXACOSAN-1-AMINIUM 4-OXIDE (3 entities in total)
• Functional Keywords: inhibitor, complex, transferase
• Biological source: Saccharomyces cerevisiae S288C (Baker's yeast); More
• Total number of polymer chains: 4
• Total formula weight: 141140.33

Authors

Xie, T.,Zhang, Z.,Fang, Q.,Gong, X. (deposition date: 2024-01-26, release date: 2024-11-27)

Primary citation

Zhang, Z.,Fang, Q.,Xie, T.,Gong, X.
Mechanism of ceramide synthase inhibition by fumonisin B 1.
Structure, 32:1419-1428.e4, 2024

PubMed Abstract: Ceramide synthases (CerSs) play crucial roles in sphingolipid metabolism and have emerged as promising drug targets for metabolic diseases, cancers, and antifungal therapy. However, the therapeutic targeting of CerSs has been hindered by a limited understanding of their inhibition mechanisms by small molecules. Fumonisin B (FB) has been extensively studied as a potent inhibitor of eukaryotic CerSs. In this study, we characterize the inhibition mechanism of FB on yeast CerS (yCerS) and determine the structures of both FB-bound and N-acyl-FB-bound yCerS. Through our structural analysis and the observation of N-acylation of FB by yCerS, we propose a potential ping-pong catalytic mechanism for FB N-acylation by yCerS. Lastly, we demonstrate that FB exhibits lower binding affinity for yCerS compared to the C26- coenzyme A (CoA) substrate, suggesting that the potent inhibitory effect of FB on yCerS may primarily result from the N-acyl-FB catalyzed by yCerS, rather than through direct binding of FB.

PubMed: 38964337
DOI: 10.1016/j.str.2024.06.002

Experimental method

ELECTRON MICROSCOPY (3.19 Å)