Structural Insights into Differences in Drug-binding Selectivity between Two Forms of Human α1-Acid Glycoprotein Genetic Variants, the A and F1*S Forms

Abstract

Human ␣ 1 -acid glycoprotein (hAGP) in serum functions as a carrier of basic drugs. In most individuals, hAGP exists as a mixture of two genetic variants, the F1*S and A variants, which bind drugs with different selectivities. We prepared a mutant of the A variant, C149R, and showed that its drug-binding properties were indistinguishable from those of the wild type. In this study, we determined the crystal structures of this mutant hAGP alone and complexed with disopyramide (DSP), amitriptyline (AMT), and the nonspecific drug chlorpromazine (CPZ). The crystal structures revealed that the drug-binding pocket on the A variant is located within an eight-stranded ␤-barrel, similar to that found in the F1*S variant and other lipocalin family proteins. However, the binding region of the A variant is narrower than that of the F1*S variant. In the crystal structures of complexes with DSP and AMT, the two aromatic rings of each drug interact with Phe-49 and Phe-112 at the bottom of the binding pocket. Although the structure of CPZ is similar to those of DSP and AMT, its fused aromatic ring system, which is extended in length by the addition of a chlorine atom, appears to dictate an alternative mode of binding, which explains its nonselective binding to the F1*S and A variant hAGPs. Modeling experiments based on the co-crystal structures suggest that, in complexes of DSP, AMT, or CPZ with the F1*S variant, Phe-114 sterically hinders interactions with DSP and AMT, but not CPZ.

Quantitative Structure – Pharmacokinetics Relationships for Plasma Protein Binding of Basic Drugs

“…The A variant has the same overall folding as the F1*S variant, but differs in the amino acid sequence and binding site topology. The binding region of A variant is narrower, and involves only lobe I and lobe II, but not lobe III (49). The crystal structures of complexes of a mutant of A variant (with undistinguishable binding affinity from the native type), and three AGP substrates give inside into the binding mode to variant A (49).…”

Quantitative Structure–pharmacokinetics Modeling of the Unbound Clearance for Neutral Drugs

“…Indeed, 60% of the drugs, containing aaaC atoms, have fu<0.1. On the other hand, the presence of aromatic rings is a prerequisite for hydrophobic, van der Waals, CH-π and π-π interactions in the binding sites of plasma proteins [27,28], and the same interactions may be involved in the binding with transport proteins and metabolizing enzymes. Descriptor SdssC_acnt encodes the number of C-atom connected with two simple and one double bond.…”

Orosomucoid binding induced amplification of inherent chirality of the immunosuppressant drug sirolimus

“…18,19 Due to sequence alterations (22 residues), the drug binding cavity of the variants differs from each other. 6 The wide, crevice-like pocket of the F1/S form is divided into three sub-chambers while the narrower cavity of the A variant consists only of two ones that accounts for their well documented distinct ligand binding properties. [20][21][22] Therefore, the interaction of sirolimus with the separated genetic variants of AAG has also been studied.…”

“…3,4 As a member of the lipocalin family, the single polypeptide chain of AAG folds into a β-barrel structure enclosing a wide, central cavity where a broad array of organic compounds can be bound. 5,6 Macrolide antibiotics are typical AAG binding agents [7][8][9] possessing a large macrocycle which is reminiscent to that of the potent immunosuppressive drug sirolimus (rapamycin). Sirolimus is a chiral, multichromophoric antifungal compound of bacterial origin consisting of triene, lactone, lactol, enone, and ketone moieties (Scheme 1).…”