9sw1

Human fumarylacetoacetate hydrolase (FAH) in complex with A4

spinqualitylabelsall models 9sw1, resolution 1.99Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9sw1 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.99Å Ligands: A1JQ6, CA, CL, GOL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Hereditary tyrosinemia type 1 (HT1) stems from the loss of fumarylacetoacetate hydrolase (FAH) activity, causing severe liver-kidney disease. Nitisinone does not restore FAH function and carries metabolic and dietary burdens. Here, we used an integrated workflow guided by X-ray structures of human FAH to obtain small-molecule pharmacological chaperones that bind with low-muM affinity and stabilize FAH. Hits were validated by NMR and isothermal titration calorimetry. Protein stabilization was assessed by DOSY-NMR and circular dichroism; functional effects were tested in FAH activity assays, a CRISPR-engineered cellular model, and testing in an animal model of HT1. Compounds shifted the G337S pathological variant toward the active dimer and slowed unfolding/aggregation, resulting in dose-dependent enhancement of FAH activity and partial rescue of FAH homeostasis in cells and the liver tissue of a mouse model of HT1. These molecules support a therapeutic approach that could complement nitisinone in HT1. Rational Design of Small-Molecule Stabilizers of Human Fumarylacetoacetate Hydrolase for the Treatment of Tyrosinemia Type I.,Scarin R, Rojas AL, Gil-Martinez J, Gomez-Galan M, Torres-Mozas A, Lopitz-Otsoa F, Fernandez-Ramos D, Jimenez-Oses G, Mato JM, Millet O J Med Chem. 2026 May 12. doi: 10.1021/acs.jmedchem.5c03489. PMID:42117404 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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