8J2F

Human neutral shpingomyelinase

Summary for 8J2F

• Entry DOI: 10.2210/pdb8j2f/pdb
• EMDB information: 35948
• Descriptor: Sphingomyelin phosphodiesterase 2, MAGNESIUM ION, HEPTANE, ... (4 entities in total)
• Functional Keywords: enzyme, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 96050.81

Authors

Zhang, S.S. (deposition date: 2023-04-14, release date: 2023-12-06, Last modification date: 2024-05-01)

Primary citation

Yi, J.,Qi, B.,Yin, J.,Li, R.,Chen, X.,Hu, J.,Li, G.,Zhang, S.,Zhang, Y.,Yang, M.
Molecular basis for the catalytic mechanism of human neutral sphingomyelinases 1 (hSMPD2).
Nat Commun, 14:7755-7755, 2023

PubMed Abstract: Enzymatic breakdown of sphingomyelin by sphingomyelinase (SMase) is the main source of the membrane lipids, ceramides, which are involved in many cellular physiological processes. However, the full-length structure of human neutral SMase has not been resolved; therefore, its catalytic mechanism remains unknown. Here, we resolve the structure of human full-length neutral SMase, sphingomyelinase 1 (SMPD2), which reveals that C-terminal transmembrane helices contribute to dimeric architecture of hSMPD2 and that D111 - K116 loop domain is essential for substrate hydrolysis. Coupled with molecular docking, we clarify the binding pose of sphingomyelin, and site-directed mutagenesis further confirms key residues responsible for sphingomyelin binding. Hybrid quantum mechanics/molecular mechanics (QM/MM) molecular dynamic (MD) simulations are utilized to elaborate the catalysis of hSMPD2 with the reported in vitro substrates, sphingomyelin and lyso-platelet activating fator (lyso-PAF). Our study provides mechanistic details that enhance our knowledge of lipid metabolism and may lead to an improved understanding of ceramide in disease and in cancer treatment.

PubMed: 38012235
DOI: 10.1038/s41467-023-43580-w

Experimental method

ELECTRON MICROSCOPY (3.07 Å)