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.
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.
Schönfeld
Dorian L
DL
Lehrstuhl für Biologische Chemie, Technische Universität München, An der Saatzucht 5, 85350 Freising-Weihenstephan, Germany.
Ravelli
Raimond B G
RB
Mueller
Uwe
U
Skerra
Arne
A
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003975:Diazepam / Q000737:chemistry / Q000378:metabolism*; D006639:Histidine / Q000737:chemistry; D006801:Humans; D008024:Ligands; D054834:Lipocalins / Q000097:blood* / Q000737:chemistry; D008958:Models, Molecular; D008967:Molecular Biology / Q000379:methods*; D008969:Molecular Sequence Data; D009961:Orosomucoid / Q000737:chemistry* / Q000378:metabolism*; D011374:Progesterone / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D040681:Structural Homology, Protein; D013499:Surface Properties; D014466:Ultraviolet Rays
D008024:Ligands; D054834:Lipocalins; D009961:Orosomucoid; D011374:Progesterone; D006639:Histidine; D003975:Diazepam