Long-range structural defects by pathogenic mutations in most severe glucose-6-phosphate dehydrogenase deficiency

This is the authors' abstract. We don't add key points for this paper.

Significance Mechanism of the loss of activity of the most severe patient-derived mutants of glucose-6-phosphate dehydrogenase (G6PD) deficiency has remained elusive despite the availability of the G6PD structures for decades. Structural and biophysical investigations have revealed a common mechanism and dynamics of how these mutations hinder the substrate-binding site, reducing enzymatic activity. These are triggered by a long-distance propagation of structural defects at the dimer interface and the binding site of the noncatalytic cofactor. These structural distortions are found among all of the class I mutants investigated, providing critical clues for drug design to address G6PD deficiency by correcting the structural defects.