PAH: Case Study

Phenylketonuria is caused by mutations in phenylalanine hydroxylase, or PAH for short. The protein is remarkable, in this context, because it is regulated in a specific way: phenylalanine, is not only its substrate, but also regulator.

The regulatory domain, with substrates in pink, and regulatory phenylalanine in pale blue:

Top active Side active

Furthermore, the regulatory domain is displaced with respect to its docked position in the inactive state.

Top inactive Side inactive

We know that the regulatory domain (N-terminal on the PAH chain) is relevant because the mutations related to phenylketonuria have been reported in this domain, shown as red sticks:

Disease related

The inactive structure has been crystallized. The active conformation, or rearrangement of domains, became known only last year through the work of two groups ...

Phenylalanine cannot be modeled in the inactive state - steric clash, so the whole structure needs to be reconstructed ‘by hand’, or at least using a mini-pipeline outside of the protocol used for the other structures in this study.