5OM8

Crystal form 2 of Alpha1-antichymotrypsin variant DBS-II-allo: an allosterically modulated drug-binding serpin for doxorubicin

5OM8 の概要

• エントリーDOI: 10.2210/pdb5om8/pdb
• 分子名称: Alpha-1-antichymotrypsin, CHLORIDE ION, 1,2-ETHANEDIOL, ... (6 entities in total)
• 機能のキーワード: serpin, alpha1-antichymotrypsin, doxorubicin-binding protein, allosterically triggered drug release, transport protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 46863.31

構造登録者

Schmidt, K.,Muller, Y.A. (登録日: 2017-07-28, 公開日: 2018-05-23, 最終更新日: 2024-05-08)

主引用文献

Schmidt, K.,Gardill, B.R.,Kern, A.,Kirchweger, P.,Borsch, M.,Muller, Y.A.
Design of an allosterically modulated doxycycline and doxorubicin drug-binding protein.
Proc. Natl. Acad. Sci. U.S.A., 115:5744-5749, 2018

PubMed Abstract: The allosteric interplay between distant functional sites present in a single protein provides for one of the most important regulatory mechanisms in biological systems. While the design of ligand-binding sites into proteins remains challenging, this holds even truer for the coupling of a newly engineered binding site to an allosteric mechanism that regulates the ligand affinity. Here it is shown how computational design algorithms enabled the introduction of doxycycline- and doxorubicin-binding sites into the serine proteinase inhibitor (serpin) family member α1-antichymotrypsin. Further engineering allowed exploitation of the proteinase-triggered serpin-typical S-to-R transition to modulate the ligand affinities. These design variants follow strategies observed in naturally occurring plasma globulins that allow for the targeted delivery of hormones in the blood. By analogy, we propose that the variants described in the present study could be further developed to allow for the delivery of the antibiotic doxycycline and the anticancer compound doxorubicin to tissues/locations that express specific proteinases, such as bacterial infection sites or tumor cells secreting matrix metalloproteinases.

PubMed: 29760101
DOI: 10.1073/pnas.1716666115

実験手法

X-RAY DIFFRACTION (2.2 Å)