3APV

Crystal structure of the A variant of human alpha1-acid glycoprotein and amitriptyline complex

3APV の概要

• エントリーDOI: 10.2210/pdb3apv/pdb
• 関連するPDBエントリー: 3APU 3APW 3APX
• 分子名称: Alpha-1-acid glycoprotein 2, Amitriptyline, ACETIC ACID, ... (4 entities in total)
• 機能のキーワード: beta barrel, plasma protein, transport protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 45997.43

構造登録者

Nishi, K.,Ono, T.,Nakamura, T.,Fukunaga, N.,Izumi, M.,Watanabe, H.,Suenaga, A.,Maruyama, T.,Yamagata, Y.,Curry, S.,Otagiri, M. (登録日: 2010-10-21, 公開日: 2011-02-23, 最終更新日: 2024-11-20)

主引用文献

Nishi, K.,Ono, T.,Nakamura, T.,Fukunaga, N.,Izumi, M.,Watanabe, H.,Suenaga, A.,Maruyama, T.,Yamagata, Y.,Curry, S.,Otagiri, M.
Structural insights into differences in drug-binding selectivity between two forms of human alpha1-acid glycoprotein genetic variants, the A and F1*S forms.
J. Biol. Chem., 286:14427-14434, 2011

PubMed Abstract: Human α(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 β-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.

PubMed: 21349832
DOI: 10.1074/jbc.M110.208926

実験手法

X-RAY DIFFRACTION (2.15 Å)