9VZS

X-ray structure of human PPARalpha ligand binding domain-10-hydroxystearic acid (10-HSA) co-crystals obtained by cross-seeding

Summary for 9VZS

• Entry DOI: 10.2210/pdb9vzs/pdb
• Descriptor: Peroxisome proliferator-activated receptor alpha, GLYCEROL, (10R)-10-hydroxyoctadecanoic acid, ... (4 entities in total)
• Functional Keywords: nuclear receptor, protein-ligand complex, ppar, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 31248.62

Authors

Liu, J.,Krause, H.M.,Kamata, S.,Honda, A.,Watase, K.,Ishii, I. (deposition date: 2025-07-23, release date: 2026-05-27)

Primary citation

Liu, J.,Li, H.,Tian, Y.,Guo, M.,Sahin, C.,Kamata, S.,Honda, A.,Campbell, J.,Shi, J.,Yurtal, E.D.,Yang, D.,Jachimowicz, M.,Hu, S.,Gong, Y.,Navarre, W.,Ishii, I.,Cummins, C.L.,Peng, H.,Wang, S.,Wang, X.,Mani, S.,Krause, H.M.
Microbial 10-oxostearic acid protects mice against colitis via the nuclear receptor PPAR alpha.
Nat Microbiol, 2026

PubMed Abstract: Interactions between the host, diet and intestinal microbiota are critical for metabolic and immune homeostasis, but the intersecting metabolites and receptors remain poorly defined. Here we identify 10-oxostearic acid (10-oxoSA), a microbial metabolite derived from oleic acid, the most abundant fatty acid in nature, as a potent and selective agonist of the lipid-sensing nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα). Biochemical and structural analyses reveal that 10-oxoSA binds PPARα with higher affinity than previously identified endogenous ligands. In a mouse model of colitis, 10-oxoSA confers protection in a PPARα-dependent manner. Multi-tissue transcriptomics show that 10-oxoSA upregulates beneficial PPARα target genes in the ileum and colon, many in previously unrecognized pathways, while also circumventing deleterious hepatic responses. Multi-omics analyses also show that prolonged oral 10-oxoSA administration is well tolerated in the gut and liver with minimal impact on gut microbiota composition. These findings establish a natural diet-microbiota-host axis with potential for anti-inflammatory interventions.

PubMed: 41951975
DOI: 10.1038/s41564-026-02321-7

Experimental method

X-RAY DIFFRACTION (1.455 Å)