globalchange  > 气候变化与战略
DOI: 10.1073/pnas.1902639116
论文题名:
Structure of full-length human phenylalanine hydroxylase in complex with tetrahydrobiopterin
作者: Flydal M.I.; Alcorlo-Pagés M.; Johannessen F.G.; Martínez-Caballero S.; Skjærven L.; Fernandez-Leiro R.; Martinez A.; Hermoso J.A.
刊名: Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
出版年: 2019
卷: 166, 期:23
起始页码: 11229
结束页码: 11234
语种: 英语
英文关键词: Allosteric regulation ; Cryo-EM ; Human phenylalanine hydroxylase ; Phenylketonuria ; X-ray crystallography
Scopus关键词: ferric ion ; phenylalanine 4 monooxygenase ; tetrahydrobiopterin ; tyrosine ; biopterin ; phenylalanine 4 monooxygenase ; sapropterin ; allosterism ; amino acid substitution ; amino terminal sequence ; Article ; catalysis ; complex formation ; conformational transition ; controlled study ; cryoelectron microscopy ; crystal structure ; enzyme active site ; enzyme analysis ; enzyme stability ; enzyme structure ; enzyme substrate complex ; gene mutation ; human ; hydrogen bond ; molecular dynamics ; negative feedback ; nonhuman ; phenylketonuria ; priority journal ; protein conformation ; protein domain ; protein protein interaction ; rat ; site directed mutagenesis ; structure analysis ; chemistry ; genetics ; molecular model ; mutation ; procedures ; Biopterin ; Humans ; Models, Molecular ; Molecular Dynamics Simulation ; Mutagenesis, Site-Directed ; Mutation ; Phenylalanine Hydroxylase ; Phenylketonurias
英文摘要: Phenylalanine hydroxylase (PAH) is a key enzyme in the catabo-lism of phenylalanine, and mutations in this enzyme cause phenylketonuria (PKU), a genetic disorder that leads to brain damage and mental retardation if untreated. Some patients benefit from supplementation with a synthetic formulation of the cofactor tetrahydrobiopterin (BH4) that partly acts as a pharmacological chaperone. Here we present structures of full-length human PAH (hPAH) both unbound and complexed with BH4 in the precatalytic state. Crystal structures, solved at 3.18-Å resolution, show the interactions between the cofactor and PAH, explaining the negative regulation exerted by BH4. BH4 forms several H-bonds with the N-terminal autoregulatory tail but is far from the catalytic FeII. Upon BH4 binding a polar and salt-bridge interaction network links the three PAH domains, explaining the stability conferred by BH4. Importantly, BH4 binding modulates the interaction between subunits, providing information about PAH allostery. Moreover, we also show that the cryo-EM structure of hPAH in absence of BH4 reveals a highly dynamic conformation for the tetramers. Structural analyses of the hPAH:BH4 subunits revealed that the substrate-induced movement of Tyr138 into the active site could be coupled to the displacement of BH4 from the precatalytic toward the active conformation, a molecular mechanism that was supported by site-directed mutagenesis and targeted molecular dynamics simulations. Finally, comparison of the rat and human PAH structures show that hPAH is more dynamic, which is related to amino acid substitutions that enhance the flexibility of hPAH and may increase the susceptibility to PKU-associated mutations. © 2019 National Academy of Sciences. All rights reserved.
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资源类型: 期刊论文
标识符: http://119.78.100.158/handle/2HF3EXSE/163599
Appears in Collections:气候变化与战略

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作者单位: Flydal, M.I., Department of Biomedicine, University of Bergen, Bergen, 5009, Norway; Alcorlo-Pagés, M., Department of Crystallography and Structural Biology, Instituto de Química-Física “Rocasolano,”, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, 28006, Spain; Johannessen, F.G., Department of Biomedicine, University of Bergen, Bergen, 5009, Norway; Martínez-Caballero, S., Department of Biomedicine, University of Bergen, Bergen, 5009, Norway; Skjærven, L., Department of Biomedicine, University of Bergen, Bergen, 5009, Norway; Fernandez-Leiro, R., Structural Biology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, 28029, Spain; Martinez, A., Department of Biomedicine, University of Bergen, Bergen, 5009, Norway; Hermoso, J.A., Department of Crystallography and Structural Biology, Instituto de Química-Física “Rocasolano,”, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, 28006, Spain

Recommended Citation:
Flydal M.I.,Alcorlo-Pagés M.,Johannessen F.G.,et al. Structure of full-length human phenylalanine hydroxylase in complex with tetrahydrobiopterin[J]. Proceedings of the National Academy of Sciences of the United States of America,2019-01-01,166(23)
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