6va7
Crystal structure of glucose-6-phosphate dehydrogenase P396L mutant in complex with catalytic NADP+
Structural highlights
DiseaseG6PD_HUMAN Defects in G6PD are the cause of chronic non-spherocytic hemolytic anemia (CNSHA) [MIM:305900. Deficiency of G6PD is associated with hemolytic anemia in two different situations. First, in areas in which malaria has been endemic, G6PD-deficiency alleles have reached high frequencies (1% to 50%) and deficient individuals, though essentially asymptomatic in the steady state, have a high risk of acute hemolytic attacks. Secondly, sporadic cases of G6PD deficiency occur at a very low frequencies, and they usually present a more severe phenotype. Several types of CNSHA are recognized. Class-I variants are associated with severe NSHA; class-II have an activity <10% of normal; class-III have an activity of 10% to 60% of normal; class-IV have near normal activity.[1] FunctionG6PD_HUMAN Produces pentose sugars for nucleic acid synthesis and main producer of NADPH reducing power. Publication Abstract from PubMedGlucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common blood disorder, presenting multiple symptoms, including hemolytic anemia. It affects 400 million people worldwide, with more than 160 single mutations reported in G6PD. The most severe mutations (about 70) are classified as class I, leading to more than 90% loss of activity of the wild-type G6PD. The crystal structure of G6PD reveals these mutations are located away from the active site, concentrating around the noncatalytic NADP(+)-binding site and the dimer interface. However, the molecular mechanisms of class I mutant dysfunction have remained elusive, hindering the development of efficient therapies. To resolve this, we performed integral structural characterization of five G6PD mutants, including four class I mutants, associated with the noncatalytic NADP(+) and dimerization, using crystallography, small-angle X-ray scattering (SAXS), cryogenic electron microscopy (cryo-EM), and biophysical analyses. Comparisons with the structure and properties of the wild-type enzyme, together with molecular dynamics simulations, bring forward a universal mechanism for this severe G6PD deficiency due to the class I mutations. We highlight the role of the noncatalytic NADP(+)-binding site that is crucial for stabilization and ordering two beta-strands in the dimer interface, which together communicate these distant structural aberrations to the active site through a network of additional interactions. This understanding elucidates potential paths for drug development targeting G6PD deficiency. Long-range structural defects by pathogenic mutations in most severe glucose-6-phosphate dehydrogenase deficiency.,Horikoshi N, Hwang S, Gati C, Matsui T, Castillo-Orellana C, Raub AG, Garcia AA, Jabbarpour F, Batyuk A, Broweleit J, Xiang X, Chiang A, Broweleit R, Vohringer-Martinez E, Mochly-Rosen D, Wakatsuki S Proc Natl Acad Sci U S A. 2021 Jan 26;118(4). pii: 2022790118. doi:, 10.1073/pnas.2022790118. PMID:33468660[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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