TY - JOUR
T1 - 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
AU - Schönfeld, Dorian L.
AU - Ravelli, Raimond B.G.
AU - Mueller, Uwe
AU - Skerra, Arne
N1 - Funding Information:
The authors wish to thank the staff at European Synchrotron Radiation Facility beamline ID23-1 for help with synchrotron diffraction data collection, and L. Chatwell for kind assistance during the refinement of the crystal structure. This work was financially supported by Pieris AG, Freising, and the Munich Center for Integrated Protein Science funded by the Deutsche Forschungsgemeinschaft.
PY - 2008/12/12
Y1 - 2008/12/12
N2 - 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.
AB - 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.
KW - UV-radiation-damage-induced phasing
KW - X-ray crystallography
KW - acute-phase protein
KW - ligand binding
KW - protein engineering
UR - http://www.scopus.com/inward/record.url?scp=54949158207&partnerID=8YFLogxK
U2 - 10.1016/j.jmb.2008.09.020
DO - 10.1016/j.jmb.2008.09.020
M3 - Article
C2 - 18823996
AN - SCOPUS:54949158207
SN - 0022-2836
VL - 384
SP - 393
EP - 405
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 2
ER -