Abstract

Phenylalanine hydroxylase (PAH) is a key enzyme in phenylalanine metabolism, crucial for maintaining appropriate phenylalanine levels in the body. Understanding its conformational dynamics is essential for elucidating its function and developing targeted therapies for phenylketonuria (PKU), a disorder caused by PAH deficiency. Here, we investigate the conformational adaptability of PAH using a cation-π sandwich as a control mechanism. Through computational modeling and experimental validation, we uncover the structural flexibility of PAH, which plays a pivotal role in substrate recognition and catalytic activity. Our findings shed light on the molecular mechanisms underlying PAH function and provide insights into the development of novel therapeutic strategies for PKU.