The drug binding site of human α1-acid glycoprotein: Insight from induced circular dichroism and electronic absorption spectra

F. Zsila, Yasunori Iwao

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Human α1-acid glycoprotein (AGP) is an important drug binding plasma protein which affects pharmacokinetical properties of various therapeutic agents. For the first time, interpretation of the induced circular dichroism (ICD) spectra of drug-AGP complexes is presented yielding valuable information on the protein binding environment. ICD spectra were obtained by novel ligands of which AGP induced optical activity have never been reported (primaquine, mefloquine, propranolol, terazosin, carbamazepine, rhodamine B) and by re-investigation of ICD spectra of protein-bound drugs published earlier (chlorpromazine, dipyridamole, prazosin). Spectroscopic features of the ICD and absorption bands of drugs combined with native AGP indicated chiral non-degenerate exciton coupling between the guest chromophore and the indole ring of an adjacent tryptophan (Trp) residue. Results of additional CD experiments performed by using recombinant AGP mutants showed no changes in the ligand binding ability of W122A in sharp contrast with the W25A which was unable to induce extrinsic CD signal with either ligand. Thus, these findings unequivocally prove that, likely via π-π stacking mechanism, Trp25 is essentially involved in the AGP binding of drugs studied here as well as of related compounds. Survey of the AGP binding data published in the literature support this conclusion. Our results provide a fast and efficient spectroscopic tool to determine the inclusion of ligand molecules into the β-barrel cavity of AGP where the conserved Trp25 is located and might be useful in ligand-binding studies of other lipocalin proteins.

Original languageEnglish
Pages (from-to)797-809
Number of pages13
JournalBBA - General Subjects
Volume1770
Issue number5
DOIs
Publication statusPublished - May 2007

Fingerprint

Dichroism
Circular Dichroism
Absorption spectra
Glycoproteins
Binding Sites
Acids
Pharmaceutical Preparations
Ligands
rhodamine B
Terazosin
Primaquine
Mefloquine
Lipocalins
Optical Rotation
Dipyridamole
Prazosin
Chlorpromazine
Carbamazepine
Chromophores
Protein Binding

Keywords

  • β-Barrel
  • Human serum α-acid glycoprotein
  • Induced circular dichroism
  • Ligand binding
  • Lipocalin
  • Non-degenerate exciton coupling
  • Tryptophan mutants

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

The drug binding site of human α1-acid glycoprotein : Insight from induced circular dichroism and electronic absorption spectra. / Zsila, F.; Iwao, Yasunori.

In: BBA - General Subjects, Vol. 1770, No. 5, 05.2007, p. 797-809.

Research output: Contribution to journalArticle

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