ArticleScientific reports2016
Structural basis for ligand-dependent dimerization of phenylalanine hydroxylase regulatory domain.
Article in Scientific reports, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 61 citations in OpenAlex.
- DNAJC12 Stabilizes Phenylalanine Hydroxylase and Facilitates Its Substrate-Dependent Activation.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Synthetic closed-loop gene circuit for phenylalanine regulation.Nucleic acids research · 2025Article
- Inhibitor-induced dimerization mediates lufotrelvir resistance in mutants of SARS-CoV-2 3C-like protease.Protein science : a publication of the Protein Society · 2025Article
- Article
- Dynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase.Nature communications · 2024Article
- In Silico Structural Protein Evaluation of the Phenylalanine Hydroxylase p.(Tyr77His) Variant Associated with Benign Hyperphenylalaninemia as Identified through Mexican Newborn Screening.Children (Basel, Switzerland) · 2023Article
- Structural mechanism for tyrosine hydroxylase inhibition by dopamine and reactivation by Ser40 phosphorylation.Nature communications · 2022Article
- Cryo-EM Structure and Activator Screening of Human Tryptophan Hydroxylase 2.Frontiers in pharmacology · 2022Article
- Blood phenylalanine reduction reverses gene expression changes observed in a mouse model of phenylketonuria.Scientific reports · 2021Article
- Manipulation of a cation-π sandwich reveals conformational flexibility in phenylalanine hydroxylase.Biochimie · 2021Article
- Modulation of Human Phenylalanine Hydroxylase by 3-Hydroxyquinolin-2(1H)-One Derivatives.Biomolecules · 2021Article
- In Silico and In Vitro Tailoring of a Chitosan Nanoformulation of a Human Metabolic Enzyme.Pharmaceutics · 2021Article
- Markov State Models to Elucidate Ligand Binding Mechanism.Methods in molecular biology (Clifton, N.J.) · 2021Review
- Protein Degradation and the Pathologic Basis of Phenylketonuria and Hereditary Tyrosinemia.International journal of molecular sciences · 2020Review
- Second-Generation Pharmacological Chaperones: Beyond Inhibitors.Molecules (Basel, Switzerland) · 2020Review
- iTRAQ-Based Proteomic Profile Analysis of the Hepatopancreas of Caribbean Spiny Lobsters Infected WithFrontiers in microbiology · 2020Article
- Structure of full-length wild-type human phenylalanine hydroxylase by small angle X-ray scattering reveals substrate-induced conformational stability.Scientific reports · 2019Article
- Biophysical characterization of full-length human phenylalanine hydroxylase provides a deeper understanding of its quaternary structure equilibrium.The Journal of biological chemistry · 2019Article
- The phenylketonuria-associated substitution R68S converts phenylalanine hydroxylase to a constitutively active enzyme but reduces its stability.The Journal of biological chemistry · 2019Article
- Conformational selection turns on phenylalanine hydroxylase.The Journal of biological chemistry · 2018Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
The multi-domain enzyme phenylalanine hydroxylase (PAH) catalyzes the hydroxylation of dietary I-phenylalanine (Phe) to I-tyrosine. Inherited mutations that result in PAH enzyme deficiency are the genetic cause of the autosomal recessive disorder phenylketonuria. Phe is the substrate for the PAH active site, but also an allosteric ligand that increases enzyme activity. Phe has been proposed to bind, in addition to the catalytic domain, a site at the PAH N-terminal regulatory domain (PAH-RD), to activate the enzyme via an unclear mechanism. Here we report the crystal structure of human PAH-RD bound with Phe at 1.8 Å resolution, revealing a homodimer of ACT folds with Phe bound at the dimer interface. This work delivers the structural evidence to support previous solution studies that a binding site exists in the RD for Phe, and that Phe binding results in dimerization of PAH-RD. Consistent with our structural observation, a disease-associated PAH mutant impaired in Phe binding disrupts the monomer:dimer equilibrium of PAH-RD. Our data therefore support an emerging model of PAH allosteric regulation, whereby Phe binds to PAH-RD and mediates the dimerization of regulatory modules that would bring about conformational changes to activate the enzyme.
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