9SZX

Human fumarylacetoacetate hydrolase (FAH) in complex with 3C9

This is a non-PDB format compatible entry.

Summary for 9SZX

• Entry DOI: 10.2210/pdb9szx/pdb
• Descriptor: Fumarylacetoacetase, 3-[(6-methylnaphthalen-2-yl)sulfonylamino]propanoic acid, GLYCEROL, ... (8 entities in total)
• Functional Keywords: human fumarylacetoacetate hydrolase (fah), hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 96249.44

Authors

Scarin, R.,Rojas, A.L.,Millet, O. (deposition date: 2025-10-16, release date: 2026-05-20)

Primary citation

Scarin, R.,Rojas, A.L.,Gil-Martinez, J.,Gomez-Galan, M.,Torres-Mozas, A.,Lopitz-Otsoa, F.,Fernandez-Ramos, D.,Jimenez-Oses, G.,Mato, J.M.,Millet, O.
Rational Design of Small-Molecule Stabilizers of Human Fumarylacetoacetate Hydrolase for the Treatment of Tyrosinemia Type I.
J.Med.Chem., 2026

PubMed Abstract: 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-μM 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.

PubMed: 42117404
DOI: 10.1021/acs.jmedchem.5c03489

Experimental method

X-RAY DIFFRACTION (2.3 Å)