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25 results on '"Rodriguez-Granillo, Agustina"'

7. Design of an in vitro biocatalytic cascade for the manufacture of islatravir

Author

Huffman, Mark A., primary, Fryszkowska, Anna, additional, Alvizo, Oscar, additional, Borra-Garske, Margie, additional, Campos, Kevin R., additional, Canada, Keith A., additional, Devine, Paul N., additional, Duan, Da, additional, Forstater, Jacob H., additional, Grosser, Shane T., additional, Halsey, Holst M., additional, Hughes, Gregory J., additional, Jo, Junyong, additional, Joyce, Leo A., additional, Kolev, Joshua N., additional, Liang, Jack, additional, Maloney, Kevin M., additional, Mann, Benjamin F., additional, Marshall, Nicholas M., additional, McLaughlin, Mark, additional, Moore, Jeffrey C., additional, Murphy, Grant S., additional, Nawrat, Christopher C., additional, Nazor, Jovana, additional, Novick, Scott, additional, Patel, Niki R., additional, Rodriguez-Granillo, Agustina, additional, Robaire, Sandra A., additional, Sherer, Edward C., additional, Truppo, Matthew D., additional, Whittaker, Aaron M., additional, Verma, Deeptak, additional, Xiao, Li, additional, Xu, Yingju, additional, and Yang, Hao, additional

Published
2019
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8. Copper-Transfer Mechanism from the Human Chaperone Atox1 to a Metal-Binding Domain of Wilson Disease Protein

Author

Rodriguez-Granillo, Agustina, Crespo, Alejandro, Estrin, Dario A., and Wittung-Stafshede, Pernilla

Abstract

The molecular details of how copper (Cu) is transferred from the human Cu chaperone Atox1 to metal-binding domains (MBDs) of P1B-type ATPases are still unclear. Here, we use a computational approach, employing quantum mechanics/molecular mechanics (QM/MM) methods, to shed light on the reaction mechanism [probable intermediates, Cu(I) coordination geometries, activation barriers, and energetics] of Cu(I) transfer from Atox1 to the fourth MBD of Wilson disease protein (WD4). Both Atox1 and WD4 have solvent-exposed metal-binding motifs with two Cys residues that coordinate Cu(I). After assessing the existence of all possible 2-, 3- and 4-coordinate Cu-intermediate species, one dominant reaction path emerged. First, without activation barrier, WD4’s Cys1 binds Cu(I) in Atox1 to form a 3-coordinated intermediate. Next, with an activation barrier of about 9.5 kcal/mol, a second 3-coordinated intermediate forms that involves both of the Cys residues in WD4 and Cys1 of Atox1. This species can then form the product by decoordination of Atox1’s Cys1 (barrier of about 8 kcal/mol). Overall, the Cu-transfer reaction from Atox1 to WD4 appears to be kinetically accessible but less energetically favorable (ΔE= 7.7 kcal/mol). Our results provide unique insights into the molecular mechanism of protein-mediated Cu(I) transfer in the secretory pathway and are in agreement with existing experimental data.

Published
2024
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12. Lysine-60 in copper chaperone Atox 1 plays an essential role in adduct formation with a target Wilson disease domain

Author

Hussain, Faiza, Rodriguez-Granillo, Agustina, and Wittung-Stafshede, Pernilla

Subjects
Copper -- Chemical properties, Lysine -- Chemical properties, Molecular dynamics -- Usage, Mutation (Biology) -- Analysis, Wilson's disease -- Research, Chemistry
Abstract

Near-ultraviolet (UV) circular dichorism along with gel filtration and molecular dynamics simulations is used as a new tool to probe chaperone-target interactions in order to show that Atox1 forms a stable Cu-dependent adduct with the fourth metal-binding domain of Wilson disease (WD4). Point-mutated Atox11 variants are used to show that the adduct forms in the absence of conserved residues M10 or T11 but K60 is essential for heterocomplex formation and Cu transfer.

Published
2009

13. Conformational dynamics of metal-binding domains in Wilson disease protein: molecular insights into selective copper transfer

Author

Rodriguez-Granillo, Agustina, Crespo, Alejandro, and Wittung-Stafshede, Pernilla

Subjects
Adenosine triphosphatase -- Research, Copper compounds -- Chemical properties, Copper compounds -- Structure, Molecular dynamics -- Usage, Biological sciences, Chemistry
Abstract

Molecular dynamic simulations was employed to study the dynamic behavior of the individual metal-binding domains (MBDs) (WD1?WD6) in ATP7B in apo forms which are human [P.sub.1B]-type ATPases involved in cellular Cu homeostasis. The results obtained provide insight into molecular features that vary distinctly among the MBDs for reported Cu transfer and protein-protein interaction specificity.

Published
2009

15. Differential roles of Met10, Thr11, and Lys60 in structural dynamics of human copper chaperone Atox1

Author

Rodriguez-Granillo, Agustina and Wittung-Stafshede, Pernilla

Subjects
Amino acids -- Structure, Amino acids -- Chemical properties, Copper -- Chemical properties, Copper -- Electric properties, Molecular chaperones -- Chemical properties, Molecular dynamics -- Usage, Biological sciences, Chemistry
Abstract

Molecular dynamics simulations are used for studying the roles of Met10, Thr11 and Lys60 in Atox1, a human copper chaperone, structural dynamics. The Atox1 residues are conserved to ensure backbone/loop flexibility, electrostatic Cu site stabilization and proper core packing and the built-in flexibility is directly linked to structural changes required for forming transient Atox1-Cu-target complexes in vivo.

Published
2009

16. Structure and dynamics of Cu(I) binding in copper chaperones Atox1 and CopZ: a computer simulation study

Author

Rodriguez-Granillo, Agustina, Wittung-Stafshede, Pernilla, Sato, Harumi, and Ozaki, Yukihiro

Subjects
Computer-generated environments -- Usage, Computer simulation -- Usage, Copper compounds -- Structure, Copper compounds -- Mechanical properties, Molecular chaperones -- Structure, Molecular chaperones -- Mechanical properties, Molecular dynamics -- Analysis, Chemicals, plastics and rubber industries
Abstract

The Cu-binding geometry and structural dynamics of two homologous Cu(I) chaperones, Homo sapiens Atox1 and Bacillus subtilis CopZ, are examined by using a combination of quantum mechanical-molecular mechanics (QM-MM) and classical molecular dynamics (MD) methods. The results have provided new insights into copper chaperone behavior with direct implications for copper transport mechanisms in vivo.

Published
2008

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