Abstract
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 language | English |
|---|---|
| Pages (from-to) | 497-507 |
| Number of pages | 11 |
| Journal | Journal of Biomolecular Structure and Dynamics |
| Volume | 34 |
| Issue number | 3 |
| Early online date | 9 Oct 2015 |
| DOIs | |
| Publication status | Published - 3 Mar 2016 |
Keywords
- allosteric Phe-binding site
- hPAH p.G46S mutation
- hyperphenylalaninemia
- molecular docking simulations
- molecular dynamics simulations