The 1.8-Å Crystal Structure of α1-Acid Glycoprotein (Orosomucoid) Solved by UV RIP Reveals the Broad Drug-Binding Activity of This Human Plasma Lipocalin

Dorian L. Schönfeld, Raimond B.G. Ravelli, Uwe Mueller, Arne Skerra

Research output: Contribution to journalArticlepeer-review

139 Scopus citations

Abstract

α1-Acid glycoprotein (AGP) is an important drug-binding protein in human plasma and, as an acute-phase protein, it has a strong influence on pharmacokinetics and pharmacodynamics of many pharmaceuticals. We report the crystal structure of the recombinant unglycosylated human AGP at 1.8 Å resolution, which was solved using the new method of UV-radiation-damage-induced phasing (UV RIP). AGP reveals a typical lipocalin fold comprising an eight-stranded β-barrel. Of the four loops that form the entrance to the ligand-binding site, loop 1, which connects β-strands A and B, is among the longest observed so far and exhibits two full turns of an α-helix. Furthermore, it carries one of the five N-linked glycosylation sites, while a second one occurs underneath the tip of loop 2. The branched, partly hydrophobic, and partly acidic cavity, together with the presumably flexible loop 1 and the two sugar side chains at its entrance, explains the diverse ligand spectrum of AGP, which is known to vary with changes in glycosylation pattern.

Original languageEnglish
Pages (from-to)393-405
Number of pages13
JournalJournal of Molecular Biology
Volume384
Issue number2
DOIs
StatePublished - 12 Dec 2008

Keywords

  • UV-radiation-damage-induced phasing
  • X-ray crystallography
  • acute-phase protein
  • ligand binding
  • protein engineering

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