气候变化领域集成服务门户(CCPortal): Long-range structural defects by pathogenic mutations in most severe glucose-6-phosphate dehydrogenase deficiency

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DOI	10.1073/pnas.2022790118
	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 A.G.; Garcia A.A.; Jabbarpour F.; Batyuk A.; Broweleit J.; Xiang X.; Chiang A.; Broweleit R.; Vöhringer-Martinez E.; Mochly-Rosen D.; Wakatsuki S.
发表日期	2021
ISSN	00278424
卷号	118 期号:4
英文摘要	Glucose-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 β-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. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Enzymopathy; G6PD deficiency; Hemolytic anemia; NADP+; Structural defects
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180901
作者单位	Life Science Center for Survival Dynamics, University of Tsukuba, Ibaraki, 305-8577, Japan; Biological Sciences Division, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, United States; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, United States; Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, United States; Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, United States; Departamento de Físico-Química, Facultad de Ciencias Químicas, Universidad de Concepción, Concepción, 94030000, Chile; Linac Coherent Light Source, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, United States
推荐引用方式 GB/T 7714	Horikoshi N.,Hwang S.,Gati C.,et al. Long-range structural defects by pathogenic mutations in most severe glucose-6-phosphate dehydrogenase deficiency[J],2021,118(4).
APA	Horikoshi N..,Hwang S..,Gati C..,Matsui T..,Castillo-Orellana C..,...&Wakatsuki S..(2021).Long-range structural defects by pathogenic mutations in most severe glucose-6-phosphate dehydrogenase deficiency.Proceedings of the National Academy of Sciences of the United States of America,118(4).
MLA	Horikoshi N.,et al."Long-range structural defects by pathogenic mutations in most severe glucose-6-phosphate dehydrogenase deficiency".Proceedings of the National Academy of Sciences of the United States of America 118.4(2021).