9t1o | pdb_00009t1o

Crystal structure of phenylalanine hydroxylase (PAH) with Belinostat

spinqualitylabelsall models 9t1o, resolution 1.94Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9t1o is a 1 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 1.94Å Ligands: 5OG, EDO, FE Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease PH4H_HUMAN Defects in PAH are the cause of phenylketonuria (PKU) [MIM:261600. PKU is an autosomal recessive inborn error of phenylalanine metabolism, due to severe phenylalanine hydroxylase deficiency. It is characterized by blood concentrations of phenylalanine persistently above 1200 mumol (normal concentration 100 mumol) which usually causes mental retardation (unless low phenylalanine diet is introduced early in life). They tend to have light pigmentation, rashes similar to eczema, epilepsy, extreme hyperactivity, psychotic states and an unpleasant 'mousy' odor. Defects in PAH are the cause of non-phenylketonuria hyperphenylalaninemia (Non-PKU HPA) [MIM:261600. Non-PKU HPA is a mild form of phenylalanine hydroxylase deficiency characterized by phenylalanine levels persistently below 600 mumol, which allows normal intellectual and behavioral development without treatment. Non-PKU HPA is usually caused by the combined effect of a mild hyperphenylalaninemia mutation and a severe one. Defects in PAH are the cause of hyperphenylalaninemia (HPA) [MIM:261600. HPA is the mildest form of phenylalanine hydroxylase deficiency. Function PH4H_HUMAN Publication Abstract from PubMed Phenylketonuria (PKU) is an inherited metabolic disorder caused by pathogenic variants in phenylalanine hydroxylase (PAH), leading to toxic phenylalanine accumulation and severe neurological complications if untreated. Current pharmacological treatment relies on tetrahydrobiopterin (BH4), which benefits only a subset of patients, highlighting a major unmet need for alternative therapies. Here, we combined high-throughput screening, computational modelling, and drug repurposing to identify pharmacological chaperones capable of rescuing PAH function. We evaluated 26 structurally diverse small molecules in HEK293T cells expressing wild-type PAH or one of eight PKU-associated variants spanning phenotypes from mild to classical disease. Chaperoning efficacy was strongly variant-dependent, and for every variant tested at least one compound produced a greater activity increase than BH4 under identical assay conditions. Notably, belinostat, a clinically approved histone deacetylase inhibitor, emerged as the most effective compound for several clinically severe variants. Mechanistically, functional rescue consistently correlated with an increased population of tetrameric, catalytically competent PAH, as quantified by mass photometry. The crystal structure of the PAH-belinostat complex (PDB ID: 9T1O), together with structural models for all compounds, provide a framework for rational optimization. These results establish a preclinical proof-of-concept for genotype-guided pharmacological chaperone therapy in PKU and support the feasibility of personalized, variant-specific treatment strategies. Variant-dependent pharmacological rescue of phenylalanine hydroxylase supports a precision therapeutic strategy for phenylketonuria.,Conde-Gimenez M, Salillas S, Galiana-Cameo M, Martinez-Olivan JE, Mahia A, Ledesma M, Galano-Frutos JJ, Maity R, Velazquez-Campoy A, Diaz-de-Villegas MD, Hurtado-Guerrero R, Sancho J Biomed Pharmacother. 2026 Jun;199:119371. doi: 10.1016/j.biopha.2026.119371. Epub , 2026 Apr 15. PMID:41990466 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Proteopedia Page Contributors and Editors (what is this?)

OCA