9L3E

Structure of GAPDH complexed with Leu-F

This is a non-PDB format compatible entry.

Summary for 9L3E

• Entry DOI: 10.2210/pdb9l3e/pdb
• Descriptor: Glyceraldehyde-3-phosphate dehydrogenase, (4~{a}~{S},5~{S},5~{a}~{R},6~{S},8~{a}~{R},9~{S},9~{a}~{S})-3,6,9-trimethyl-5-[(1~{S},2~{R})-2-methyl-4-(3-methylfuran-2-yl)-1-oxidanyl-butyl]-3,4,5~{a},6,7,8,8~{a},9-octahydro-2~{H}-cyclopenta[g]chromene-4~{a},5,9~{a}-triol, ZINC ION, ... (8 entities in total)
• Functional Keywords: gapdh, immune system, compound target
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 149495.57

Authors

Gong, L. (deposition date: 2024-12-18, release date: 2025-08-06)

Primary citation

Zhou, T.T.,Zheng, Y.,Zhang, M.W.,Gong, L.H.,Guo, K.,He, X.P.,Liu, Y.C.,Gershenzon, J.,Liu, Y.,Li, S.H.
Plant defense-directed discovery of a natural anti-psoriasis agent targeting GAPDH.
Sci Adv, 11:eadw2578-eadw2578, 2025

PubMed Abstract: Elucidating the ecological functions of natural products in plant adaptive mechanisms is an emerging means of discovering lead compounds. Here, we show an undescribed plant glandular trichome-specific defense sesterterpenoid, leucosceptrine F (leu-F), exhibiting potent anti-inflammatory activity by modulating both innate and adaptive immune responses. Leu-F irreversibly binds to glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a cross-kingdom glycolytic enzyme and a promising therapeutic target in autoimmune diseases. Crystal structure of the GAPDH-leu-F complex reveals the formation of a covalent bond between leu-F and the Cys residue. Leu-F notably attenuated glycolysis and concurrently diminished GAPDH-mediated stabilization of activated protein kinase B (AKT). Both leu-F and the total sesterterpenoid extract of demonstrated notable therapeutic efficacy and safety in mouse models of psoriasis and experimental autoimmune encephalomyelitis. This study underscores leu-F as a promising lead compound for autoimmune disease treatment and provides a compelling example of drug discovery inspired by chemical ecology.

PubMed: 40712011
DOI: 10.1126/sciadv.adw2578

Experimental method

X-RAY DIFFRACTION (1.77 Å)