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dc.contributor.author
Tossounian, Maria Armineh  
dc.contributor.author
Hristov, Stefan Denchev  
dc.contributor.author
Semelak, Jonathan Alexis  
dc.contributor.author
Yu, Bess Yi Kun  
dc.contributor.author
Baczynska, Maria  
dc.contributor.author
Zhao, Yuhan  
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Estrin, Dario Ariel  
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Trujillo, Madia  
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Filonenko, Valeriy  
dc.contributor.author
Gouge, Jerome  
dc.contributor.author
Gout, Ivan  
dc.date.available
2024-02-27T11:24:05Z  
dc.date.issued
2023-05  
dc.identifier.citation
Tossounian, Maria Armineh; Hristov, Stefan Denchev; Semelak, Jonathan Alexis; Yu, Bess Yi Kun; Baczynska, Maria; et al.; A Unique Mode of Coenzyme A Binding to the Nucleotide Binding Pocket of Human Metastasis Suppressor NME1; Multidisciplinary Digital Publishing Institute; International Journal of Molecular Sciences; 24; 11; 5-2023; 1-17  
dc.identifier.issn
1422-0067  
dc.identifier.uri
http://hdl.handle.net/11336/228510  
dc.description.abstract
Coenzyme A (CoA) is a key cellular metabolite which participates in diverse metabolic pathways, regulation of gene expression and the antioxidant defense mechanism. Human NME1 (hNME1), which is a moonlighting protein, was identified as a major CoA-binding protein. Biochemical studies showed that hNME1 is regulated by CoA through both covalent and non-covalent binding, which leads to a decrease in the hNME1 nucleoside diphosphate kinase (NDPK) activity. In this study, we expanded the knowledge on previous findings by focusing on the non-covalent mode of CoA binding to the hNME1. With X-ray crystallography, we solved the CoA bound structure of hNME1 (hNME1-CoA) and determined the stabilization interactions CoA forms within the nucleotide-binding site of hNME1. A hydrophobic patch stabilizing the CoA adenine ring, while salt bridges and hydrogen bonds stabilizing the phosphate groups of CoA were observed. With molecular dynamics studies, we extended our structural analysis by characterizing the hNME1-CoA structure and elucidating possible orientations of the pantetheine tail, which is absent in the X-ray structure due to its flexibility. Crystallographic studies suggested the involvement of arginine 58 and threonine 94 in mediating specific interactions with CoA. Site-directed mutagenesis and CoA-based affinity purifications showed that arginine 58 mutation to glutamate (R58E) and threonine 94 mutation to aspartate (T94D) prevent hNME1 from binding to CoA. Overall, our results reveal a unique mode by which hNME1 binds CoA, which differs significantly from that of ADP binding: the α- and β-phosphates of CoA are oriented away from the nucleotide-binding site, while 3′-phosphate faces catalytic histidine 118 (H118). The interactions formed by the CoA adenine ring and phosphate groups contribute to the specific mode of CoA binding to hNME1.  
dc.format
application/pdf  
dc.language.iso
eng  
dc.publisher
Multidisciplinary Digital Publishing Institute  
dc.rights
info:eu-repo/semantics/openAccess  
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/  
dc.subject
COALATION  
dc.subject
COENZYME A  
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METASTASIS SUPPRESSOR  
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MOLECULAR DYNAMICS  
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NDPK-A STRUCTURE  
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NM23-H1  
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NME1  
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NUCLEOTIDE BINDING  
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PROTEIN-METABOLITE REGULATION  
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X-RAY CRYSTALLOGRAPHY  
dc.subject.classification
Otras Ciencias Químicas  
dc.subject.classification
Ciencias Químicas  
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CIENCIAS NATURALES Y EXACTAS  
dc.title
A Unique Mode of Coenzyme A Binding to the Nucleotide Binding Pocket of Human Metastasis Suppressor NME1  
dc.type
info:eu-repo/semantics/article  
dc.type
info:ar-repo/semantics/artículo  
dc.type
info:eu-repo/semantics/publishedVersion  
dc.date.updated
2024-02-26T11:08:59Z  
dc.journal.volume
24  
dc.journal.number
11  
dc.journal.pagination
1-17  
dc.journal.pais
Suiza  
dc.description.fil
Fil: Tossounian, Maria Armineh. Colegio Universitario de Londres; Reino Unido  
dc.description.fil
Fil: Hristov, Stefan Denchev. Colegio Universitario de Londres; Reino Unido  
dc.description.fil
Fil: Semelak, Jonathan Alexis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina  
dc.description.fil
Fil: Yu, Bess Yi Kun. Colegio Universitario de Londres; Reino Unido  
dc.description.fil
Fil: Baczynska, Maria. Colegio Universitario de Londres; Reino Unido  
dc.description.fil
Fil: Zhao, Yuhan. Colegio Universitario de Londres; Reino Unido  
dc.description.fil
Fil: Estrin, Dario Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina  
dc.description.fil
Fil: Trujillo, Madia. Universidad de la República; Uruguay  
dc.description.fil
Fil: Filonenko, Valeriy. Colegio Universitario de Londres; Reino Unido  
dc.description.fil
Fil: Gouge, Jerome. Colegio Universitario de Londres; Reino Unido  
dc.description.fil
Fil: Gout, Ivan. Colegio Universitario de Londres; Reino Unido  
dc.journal.title
International Journal of Molecular Sciences  
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.mdpi.com/1422-0067/24/11/9359  
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.3390/ijms24119359