Human α1-acid glycoprotein (AAG), also known as orosomucoid, is the most important component of the positive acute phase proteins of the plasma [1] and [2]. The normal concentration of AAG (0.5–1.4 mg/mL; 12–30 μM), which accounts for about 1% to 3% of total protein can rise to three or fourfolds within a day following the unset of an acute phase response [3]. The single polypeptide chain of AAG (183 residues, Mw = 36,000–44,000) is heavily glycosylated, which is responsible for protein microheterogeneity [2]. In addition, the polypeptide chain of AAG exists in two main polymorphic forms called ‘F1/S’ (ORM1) and ‘A’ (ORM2) genetic variants encoded by two different genes having 22/183
signal transducer and activator of transcription 5 (322-343) acetyl substitutions [4]. The ‘F1/S’ isoform predominates in a mean molar ratio of 3:1 over ‘A’ in normal human plasma [5] but variations of this ratio have been reported under pathological conditions [6]. Due to the carbohydrate-based microheterogeneity, the structure of AAG proved to be refractory for X-ray crystallographic determination. Based on genetic analysis, AAG was classified as the member of the lipocalin protein family [7]. Lipocalins, distributed in animals, plants, and even bacteria, are small, single domain, secreted proteins that bind and transport generally hydrophobic, biologically active
molecules (e.g. retinoids, steroids) [8]. Ten lipocalins were found in the human body to date [7] among which X-ray/NMR structures of several proteins have been solved [9]. Despite the less than 20% overall sequence similarity among lipocalins, they share a conserved structural motif called the lipocalin fold, which is common to this group of proteins. It is a β-barrel formed by eight antiparallel β-strands winding around a central axis. At the open end of the resulting cup shaped pocket these strands are connected in a pair-wise fashion by four loops, which form the entrance to the central cavity (calyx), the principal binding site of lipophilic ligands [9].