Abstract
Phenylalanine hydroxylase catalyzes a critical step in the phenylalanine catabolic pathway, and impairment of the human enzyme is linked to phenylketonuria. Phenylalanine is also a positive allosteric regulator of the enzyme, and the allosteric binding site has been determined by crystallography. However, the allosteric activation mechanism remains unclear. Using large-scale simulations to explore how phenylalanine binds to the regulatory site, Ge et al. discovered gating motions of the protein that suggest a conformational selection mechanism.
Highlights
Phenylalanine hydroxylase catalyzes a critical step in the phenylalanine catabolic pathway, and impairment of the human enzyme is linked to phenylketonuria
As revealed by the recently solved crystal structure of the Phe-bound ACT domain dimer, the Phe-binding allosteric site is positioned at an intersubunit interface located between the two ACT domains and is well-defined in activated phenylalanine hydroxylase (PAH) but absent in the resting state of the enzyme (1)
Markov State Models (MSMs) (6) provide a powerful approach to address this challenge by modeling long timescale dynamics from many short molecular dynamics (MD) simulations and have been widely applied to study protein conformational changes (7)
Summary
Phenylalanine hydroxylase catalyzes a critical step in the phenylalanine catabolic pathway, and impairment of the human enzyme is linked to phenylketonuria. PAH binds Phe at its active site, and at a second site that allosterically regulates PAH. As revealed by the recently solved crystal structure of the Phe-bound ACT domain dimer, the Phe-binding allosteric site is positioned at an intersubunit interface located between the two ACT domains and is well-defined in activated PAH but absent in the resting state of the enzyme (1).
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