Figure 1.

The comparative interactions of the AK1 isoforms with the analog substrates (Ap5A or B4P) after redocking. The redocked conformations are shown in yellow. (a) zebrafish AK1 (PDB ID 5XZ2); (b) human AK1 (PDB ID 1X83); (c) human AK1 (PDB ID 2C95).
Figure 2.

(a) The interactions comparative of the human AK2 (PDB ID 2C9Y) with the B4P after redocking; (b) The comparative interactions of the human AK5 (PDB ID 2BWJ) with the AMP after redocking. The redocked conformations are shown in yellow.
Figure 3.

The comparative interactions of the bacterial AKs with the analog substrate Ap5A after redocking. The redocked conformations are shown in yellow. (a) E.coli AK (PDB ID 3HPQ); (b) B.stearothermophilus AK (PDB ID 1ZIP).
Figure 4.

Interactions of ionized amantadine with human AK1, PDB ID 1Z83. (a) 3D display of ionized amantadine interaction as ligand with the 1Z83 residues; (b) code color for interactions: in green are shown conventional hydrogen bonds, light green – van der Waals forces, mauve – alkyl hydrophobic interactions, red – unfavorable positive-positive interactions; (c) the distances (Å) of the 1Z83 - ionized amantadine interactions.
Figure 5.

Interactions of ionized amantadine with human AK1, PDB ID 2C95. (a) 3D display of ionized amantadine interaction as ligand with the 2C95 residues; (b) code color for interactions: in orange are shown the salt bridge, light green – van der Waals forces, mauve – alkyl hydrophobic interactions; (c) the distances (Å) of the 2C95 - ionized amantadine interactions.
Figure 6.

Interactions of ionized amantadine with zebrafish AK1, PDB ID 5XZ2. (a) 3D display of ionized amantadine interaction as ligand with the 5XZ2 residues; (b) code color for interactions: in green are shown conventional hydrogen bonds, orange – salt bridge, light green – van der Waals forces, mauve – alkyl hydrophobic interactions; (c) the distances (Å) of the 5XZ2 - ionized amantadine interactions.
Figure 7.

Interactions of ionized amantadine with human AK2, PDB ID 2C9Y. (a) 3D display of ionized amantadine interaction as ligand with the 2C9Y residues; (b) code color for interactions: in green are shown conventional hydrogen bonds, orange – salt bridge, light green – van der Waals forces, mauve – alkyl hydrophobic interactions; (c) the distances (Å) of the 2C9Y-ionized amantadine interactions.
Figure 8.

Interactions of amantadine with human AK5, PDB ID 2BWJ. (a) 3D display of ionized amantadine interaction as ligand with the 2BWJ residues; (b) code color for interactions: in orange are shown salt bridge, light green – van der Waals forces, mauve – alkyl hydrophobic interactions, red – unfavorable donor-donor interactions; (c) the distances (Å) of the 2BWJ - ionized amantadine interactions.
Figure 9.

Interactions of ionized amantadine with AK from E.coli, PDB ID 3HPQ. (a) 3D display of amantadine interaction as ligand with the 3HPQ residues; (b) code color for interactions: in green are shown conventional hydrogen bonds, orange – salt bridge, light green – van der Waals forces, mauve – alkyl hydrophobic interactions; (c) the distances (Å) of the 3HPQ - ionized amantadine interactions.
Figure 10.

Interactions of ionized amantadine with AK from B.stearothermophilus, PDB ID 1ZIP. (a) 3D display of amantadine interaction as ligand with the 1ZIP residues; (b) code color for interactions: in green are shown conventional hydrogen bonds, orange – salt bridge, light green – van der Waals forces, mauve – alkyl hydrophobic interactions; (c) the distances (Å) of the 1ZIP - ionized amantadine interactions.
Figure 11.

Interactions of unionized and ionized amantadine with AKs. (a) human AK1 (PDB ID 2C95); (b) human AK1 (PDB ID 1Z85) (c) zebrafish AK1 (PDB ID 5XZ2); (d) human AK2 (PDB ID 2C9Y); (e) human AK5 (PDB ID 2BWJ) (f) AK from E.coli (PDB ID 3HPQ); (g) AK from B.stearothermophilus (PDB ID 1ZIP); unionized amantadine is shown in yellow.
Figure 12.

Multiple sequence alignment of the AKs sequences. In gray background are marked the residues belong to Walker A motif – phosphate-binding loop or P-loop; in yellow background is marked the NMP binding region and the residues that belong to AMP binding region are italic-bolded; in blue background is marked the LID region; with red are marked the residues (van der Waals, conventional hydrogen bond or alkyl interactions) which interact with amantadine ionized form (with –NH3+ group); the residues which interact with amantadine unionized form (with –NH2 group) are bolded-underlined; the residues which interact with amantadine unionized and ionized are red and bolded-underlined; AKEC is AK from E.coli; AKBS is AK from B.stearothermophilus; with dot “.” are marked the semi-conservative replacements; with colon “:” are marked the conservative replacements; with “*” are marked the identities of the residues.
Figure 13.

Interactions of ionized amantadine with APRT co-crystallized with AMP, PDB ID 1ZN9. (a) 3D display of the amantadine (shows in yellow) and AMP in binding pocket; (b) code color for interactions: in green are shown conventional hydrogen bonds, orange – salt bridge, mauve – alkyl hydrophobic interactions; (c) the distances (Å) of the 1ZN9 - ionized amantadine interactions.
Figure 14.

Interactions of ionized amantadine with APRT co-crystallized with AMP, PDB ID 1ZN8. (a) 3D display of the amantadine (shows in yellow) and AMP in binding pocket; (b) code color for interactions: in orange are shown the salt bridges, light green – van der Waals forces, mauve – alkyl hydrophobic interactions; (c) the distances (Å) of the 1ZN8 - ionized amantadine interactions.
Figure 15.

Interactions of ionized amantadine with APRT co-crystallized with AMP, PDB ID 1ORE. (a) 3D display of the amantadine (shows in yellow) and AMP in binding pocket; (b) code color for interactions: in orange are shown the salt bridges, light green – van der Waals forces, mauve – alkyl hydrophobic interactions; (c) the distances (Å) of the 1ORE - ionized amantadine interactions.
Figure 16.

Interactions of ionized amantadine with APRT co-crystallized with AMP, PDB ID 4X44. (a) 3D display of the amantadine (shows in yellow) and AMP in binding pocket; (b) code color for interactions: in orange are shown the salt bridges, light green – van der Waals forces, mauve – alkyl hydrophobic interactions; (c) the distances (Å) of the 4X44 - ionized amantadine interactions.
Figure 17.

Interactions of ionized amantadine with APRT co-crystallized with adenine, PDB ID 6FCI. (a) 3D display of the amantadine (shows in yellow) and adenine in binding pocket; (b) code color for interactions: in orange are shown the salt bridges, light green – van der Waals forces, mauve – alkyl hydrophobic interactions; (c) the distances (Å) of the 6FCI - ionized amantadine interactions.
Figure 18.

Interactions of ionized amantadine with APRT co-crystallized with adenine, PDB ID 1ZN7. (a) 3D display of the amantadine (shows in yellow) and adenine in binding pocket; (b) code color for interactions: in orange are shown the salt bridges, light green – van der Waals forces, mauve – alkyl hydrophobic interactions; (c) the distances (Å) of the 1ZN7 - ionized amantadine interactions.
Figure 19.

The involvement of human AK1 and human AK2 in PD, inflammation, and muscle activity. The amantadine treatment efficacy in PD developed the hypothesis that amantadine – AK interactions.
Acknowledgments
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