Contribution of Phe112, Ser114, and Tyr115 to Drug-Binding Selectivity in the A Variant of α 1 -Acid Glycoprotein.

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  • Additional Information
    • Source:
      Publisher: American Chemical Society Country of Publication: United States NLM ID: 101197791 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1543-8392 (Electronic) Linking ISSN: 15438384 NLM ISO Abbreviation: Mol Pharm Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, DC : American Chemical Society, c2004-
    • Subject Terms:
      Orosomucoid*/metabolism ; Orosomucoid*/genetics ; Orosomucoid*/chemistry ; Protein Binding*; Humans ; Binding Sites ; Phenylalanine/chemistry ; Phenylalanine/genetics ; Phenylalanine/metabolism ; Tyrosine/chemistry ; Tyrosine/metabolism ; Tyrosine/genetics ; Mutation ; Serine/metabolism ; Serine/genetics ; Serine/chemistry ; Anti-Arrhythmia Agents/chemistry ; Anti-Arrhythmia Agents/metabolism
    • Abstract:
      The plasma protein α 1 -acid glycoprotein (AGP) primarily affects the pharmacokinetics of basic drugs. There are two AGP variants in humans, A and F1*S, exhibiting distinct drug-binding selectivity. Elucidation of the drug-binding selectivity of human AGP variants is essential for drug development and personalized drug therapy. Herein, we aimed to establish the contribution of amino acids 112 and 114 of human AGP to drug-binding selectively. Both amino acids are located in the drug-binding region and differ between the variants. Phe112/Ser114 of the A variant and its equivalent residues in the F1*S variant (Leu112/Phe114) were swapped with each other. Binding experiments were then conducted using the antiarrhythmic drug disopyramide, which selectively binds to the A variant. A significant decrease in the bound fraction was observed in each singly mutated A protein (Phe112Leu or Ser114Phe). Moreover, the bound fraction of the double A mutant (Phe112Leu/Ser114Phe) was decreased to that of wild-type F1*S. Intriguingly, the double F1*S mutant (Leu112Phe/Phe114Ser), in which residues were swapped with those of the A variant, showed only partial restoration in binding. The triple F1*S mutant (Leu112Phe/Phe114Ser/Asp115Tyr), where position 115 is thought to contribute to the difference in pocket size between variants, showed a further recovery in binding to 70% of that of wild-type A. These results were supported by thermodynamic analysis and acridine orange binding, which selectively binds the A variant. Together, these data indicate that, in addition to direct interaction with Phe112 and Ser114, the binding pocket size contributed by Tyr115 is important for the drug-binding selectivity of the A variant.
    • Contributed Indexing:
      Keywords: disopyramide; drug-binding; isothermal titration calorimetry; ultrafiltration; variant selectivity; α1-acid glycoprotein
    • Accession Number:
      0 (Orosomucoid)
      47E5O17Y3R (Phenylalanine)
      42HK56048U (Tyrosine)
      452VLY9402 (Serine)
      0 (Anti-Arrhythmia Agents)
    • Publication Date:
      Date Created: 20240701 Date Completed: 20240805 Latest Revision: 20240805
    • Publication Date:
      20240805
    • Accession Number:
      10.1021/acs.molpharmaceut.4c00428
    • Accession Number:
      38949624