The 1.8-A crystal structure of alpha1-acid glycoprotein (Orosomucoid) solved by UV RIP reveals the broad drug-binding activity of this human plasma lipocalin

J Mol Biol. 2008 Dec 12;384(2):393-405. doi: 10.1016/j.jmb.2008.09.020. Epub 2008 Sep 16.

Abstract

Alpha(1)-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 A 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 beta-barrel. Of the four loops that form the entrance to the ligand-binding site, loop 1, which connects beta-strands A and B, is among the longest observed so far and exhibits two full turns of an alpha-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Crystallography, X-Ray
  • Diazepam / chemistry
  • Diazepam / metabolism*
  • Histidine / chemistry
  • Humans
  • Ligands
  • Lipocalins / blood*
  • Lipocalins / chemistry
  • Models, Molecular
  • Molecular Biology / methods*
  • Molecular Sequence Data
  • Orosomucoid / chemistry*
  • Orosomucoid / metabolism*
  • Progesterone / chemistry
  • Progesterone / metabolism
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Sequence Alignment
  • Structural Homology, Protein
  • Surface Properties
  • Ultraviolet Rays*

Substances

  • Ligands
  • Lipocalins
  • Orosomucoid
  • Progesterone
  • Histidine
  • Diazepam

Associated data

  • PDB/3BX6