9T5S
Crystal structure of human PPARalpha in complex with co-activator PGC-1 alpha peptide and bempedoic acid
This is a non-PDB format compatible entry.
Summary for 9T5S
| Entry DOI | 10.2210/pdb9t5s/pdb |
| Descriptor | Peroxisome proliferator-activated receptor alpha, Peroxisome proliferator-activated receptor gamma coactivator 1-alpha, Bempedoic acid, ... (4 entities in total) |
| Functional Keywords | peroxisome proliferator-activated receptor alpha (pparalpha), bempedoic acid (ba), nuclear receptor, activator, transcription |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 70314.00 |
| Authors | Useini, A.,Strater, N.,Kuenze, G.,Heiker, J.T.,Sheikh, B.N. (deposition date: 2025-11-05, release date: 2025-12-17, Last modification date: 2026-04-22) |
| Primary citation | Papa, C.,Rose, A.,Martin, H.N.G.,Useini, A.,Geier, F.,Liao, L.,Rodriguez-Aguilera, J.R.,Valina-Allo, P.,Hoffmann, A.,Tvardovskiy, A.,Zulfqar, F.,Zimmerman, A.,Schicht, G.,Ott, F.,Korner, C.,Engelmann, B.,Rolle-Kampczyk, U.,von Bergen, M.,Meier, M.,Bartke, T.,Seehofer, D.,Kloting, N.,Matz-Soja, M.,Damm, G.,Boeckel, J.N.,Buescher, J.M.,Bluher, M.,Laufs, U.,Bondareva, O.,Strater, N.,Kunze, G.,Heiker, J.T.,Sheikh, B.N. Bempedoic acid directly binds and activates PPAR alpha. Cell Metab., 38:824-, 2026 Cited by PubMed Abstract: Bempedoic acid (BA) is a recently approved drug that lowers cholesterol and hepatic lipids, yet its mechanism of action remains incompletely understood. Here, we combine transcriptomic, biochemical, and structural approaches to show that BA directly binds to and activates peroxisome proliferator-activated receptor alpha (PPARα). BA treatment robustly induced PPARα signaling and fatty acid oxidation in primary hepatocytes and mouse liver. Through X-ray crystallography, we uncovered that BA binds to the ligand-binding domain of PPARα and stabilizes its active conformation. BA activated PPARα target genes independently of very-long-chain acyl-coenzyme A (CoA) synthetase (ACSVL1), the liver-enriched enzyme that converts BA to its bempedoyl-CoA form. Notably, BA-mediated induction of fatty acid oxidation required PPARα. Together, this work reveals direct PPARα activation as a key mechanism of BA action, providing a molecular basis for its lipid-lowering effects and suggesting broader therapeutic potential beyond the liver. PubMed: 41592562DOI: 10.1016/j.cmet.2025.12.018 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.74 Å) |
Structure validation
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