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Long-range structural defects by pathogenic mutations in most severe glucose-6-phosphate dehydrogenase deficiency
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- Naoki Horikoshi
- Life Science Center for Survival Dynamics, University of Tsukuba, Ibaraki 305-8577, Japan;
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- Sunhee Hwang
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305;
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- Cornelius Gati
- Biological Sciences Division, SLAC National Accelerator Laboratory, Menlo Park, CA 94025;
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- Tsutomu Matsui
- Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Menlo Park, CA 94025;
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- Carlos Castillo-Orellana
- Departamento de Físico-Química, Facultad de Ciencias Químicas, Universidad de Concepción, Concepción 94030000, Chile;
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- Andrew G. Raub
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305;
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- Adriana A. Garcia
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305;
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- Fatemeh Jabbarpour
- Biological Sciences Division, SLAC National Accelerator Laboratory, Menlo Park, CA 94025;
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- Alexander Batyuk
- Linac Coherent Light Source, SLAC National Accelerator Laboratory, Menlo Park, CA 94025
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- Joshua Broweleit
- Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305;
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- Xinyu Xiang
- Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305;
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- Andrew Chiang
- Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305;
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- Rachel Broweleit
- Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305;
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- Esteban Vöhringer-Martinez
- Departamento de Físico-Química, Facultad de Ciencias Químicas, Universidad de Concepción, Concepción 94030000, Chile;
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- Daria Mochly-Rosen
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305;
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- Soichi Wakatsuki
- Biological Sciences Division, SLAC National Accelerator Laboratory, Menlo Park, CA 94025;
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Description
<jats:title>Significance</jats:title> <jats:p>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.</jats:p>
Journal
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 118 (4), 2021-01-18
Proceedings of the National Academy of Sciences
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Keywords
- Models, Molecular
- Protein Conformation, alpha-Helical
- Proline
- Genetic Vectors
- Coenzymes
- Gene Expression
- Glucosephosphate Dehydrogenase
- Molecular Dynamics Simulation
- Crystallography, X-Ray
- Substrate Specificity
- Leucine
- Escherichia coli
- Humans
- Protein Interaction Domains and Motifs
- Cloning, Molecular
- Binding Sites
- Recombinant Proteins
- Kinetics
- Glucosephosphate Dehydrogenase Deficiency
- Mutation
- Protein Conformation, beta-Strand
- Protein Multimerization
- NADP
- Protein Binding
Details 詳細情報について
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- CRID
- 1360009142731617792
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- ISSN
- 10916490
- 00278424
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- PubMed
- 33468660
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- Article Type
- journal article
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- Data Source
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- Crossref
- KAKEN
- OpenAIRE
