Towards the identification of the allosteric Phe-binding site in phenylalanine hydroxylase

Carla Carluccio, Franca Fraternali, Franco Salvatore, Arianna Fornili, Adriana Zagari

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)497-507
Number of pages11
JournalJournal of Biomolecular Structure and Dynamics
Issue number3
Publication statusPublished - 2016


  • Allosteric Regulation
  • Allosteric Site
  • Binding Sites
  • Catalytic Domain
  • Humans
  • Models, Molecular
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Mutation
  • Phenylalanine
  • Phenylalanine Hydroxylase
  • Protein Binding
  • Protein Conformation
  • Protein Multimerization
  • Structure-Activity Relationship
  • Journal Article
  • Research Support, Non-U.S. Gov't


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