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

• DOI: 10.1073/pnas.2022790118
• Publication Date: 2021-01-19T22:10:11Z
• Authors: Naoki Horikoshi; Sunhee Hwang; Cornelius Gati; Tsutomu Matsui; Carlos Castillo-O...; Andrew G. Raub; Adriana A. Garcia; Fatemeh Jabbarpour; Alexander Batyuk; Joshua Broweleit; Xinyu Xiang; Andrew Chiang; Rachel Broweleit; Esteban Vöhringer...; Daria Mochly-Rosen; Soichi Wakatsuki
• Keywords: Models, Molecular; Protein Conformation, alpha-Helical; 0301 basic medicine; Binding Sites; Proline; Genetic Vectors; Coenzymes; Gene Expression; Biological Sciences; Glucosephosphate Dehydrogenase; Molecular Dynamics Simulation; Crystallography, X-Ray; 3. Good health; Kinetics; 03 medical and health sciences; Glucosephosphate Dehydrogenase Deficiency; Leucine; Mutation; Escherichia coli; Humans; Protein Conformation, beta-Strand; Cloning, Molecular; NADP; Protein Binding

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.