Towards the identification of the allosteric Phe-binding site in phenylalanine hydroxylase
| Autor: | Carla Carluccio, Franca Fraternali, Arianna Fornili, Adriana Zagari, Francesco Salvatore |
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| Rok vydání: | 2015 |
| Předmět: |
Models
Molecular 0301 basic medicine Phenylalanine hydroxylase Protein Conformation Phenylalanine Allosteric regulation Molecular Dynamics Simulation Biology Structure-Activity Relationship 03 medical and health sciences Protein structure Hyperphenylalaninemia Allosteric Regulation Structural Biology Catalytic Domain medicine Humans Binding site Molecular Biology chemistry.chemical_classification Binding Sites Phenylalanine Hydroxylase Cooperative binding General Medicine medicine.disease Molecular Docking Simulation 030104 developmental biology Enzyme Biochemistry Allosteric enzyme chemistry Mutation biology.protein Protein Multimerization Allosteric Site Protein Binding |
| Zdroj: | Journal of Biomolecular Structure and Dynamics. 34:497-507 |
| ISSN: | 1538-0254 0739-1102 |
| DOI: | 10.1080/07391102.2015.1052016 |
| Popis: | The enzyme phenylalanine hydroxylase (PAH) is defective in the inherited disorder phenylketonuria. PAH, a tetrameric enzyme, is highly regulated and displays positive cooperativity for its substrate, Phe. Whether Phe binds to an allosteric site is a matter of debate, despite several studies worldwide. To address this issue, we generated a dimeric model for Phe–PAH interactions, by performing molecular docking combined with molecular dynamics simulations on human and rat wild-type sequences and also on a human G46S mutant. Our results suggest that the allosteric Phe-binding site lies at the dimeric interface between the regulatory and the catalytic domains of two adjacent subunits. The structural and dynamical features of the site were characterized in depth and described. Interestingly, our findings provide evidence for lower allosteric Phe-binding ability of the G46S mutant than the human wild-type enzyme. This also explains the disease-causing nature of this mutant. |
| Databáze: | OpenAIRE |
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