2つのビスホスフォナート:1-デオキシヒルロース-5-ホスファート還元イソメラーゼ複合体の結晶構造
Shunsuke Yajima1, Kodai Hara, John M Sanders
1Department of Bioscience, Tokyo University of Agriculture, Setagaya-ku, Tokyo 156-8502, Japan.
Journal of the American Chemical Society
|September 2, 2004
まとめ
2つのビスホスフォネートは,1-デオキシヒルロース-5-ホスファート還元イソメラーゼ (DXR) で結晶化され,結合相互作用が明らかになりました. これらの構造は,抗感染剤として新しいビスホスフォナートDXR阻害剤を開発する可能性を秘めています.
科学分野:
- バイオケミストリー バイオケミストリー
- 構造生物学 構造生物学とは
- ドラッグ・ディスカバリー・ドリッグ・ディスカバリー・ドリッグ・ディスカバリー・ドリッグ・ディスカバリー
背景:
- 1-デオキシジルロース-5-リン酸還元イソメラーゼ (DXR) は,抗マラリア薬の開発において重要な酵素であり,検証された標的である.
- ビスホスフォネートは,潜在的な治療用途を持つ化合物のクラスです.
- 酵素-阻害剤の相互作用を理解することは,合理的な薬剤設計の鍵です.
研究 の 目的:
- 2つの新しいビスフォスフォネートに結合したDXRの結晶構造を決定する.
- DXR活性部位内のこれらのビスフォスフォネートの結合モードと相互作用を解明する.
- 抗感染症療法におけるDXR阻害剤としてのビスホスフォネートの可能性を調査する.
主な方法:
- 単結晶X線結晶学を用いて,高解像度構造が得られた.
- 結晶学的データを分析し,リガンド-タンパク質の相互作用を特定しました.
- 酵素表記:1-デオキシジルロース-5-ホスファート還元イソメラーゼ (DXR,EC 1.1.1.267).
主要な成果:
- [(1-イソキノリニラミノ) メチレン]-1,1-ビスホスフォネートと[[(5-クロロ-2-ピリジニル) アミノ]メチレン]-1,1-ビスホスフォネートと複合したDXRの結晶構造が得られた.
- 両方のビスホスフォン酸は,DXRのフォスミドミシン結合部位と結合する.
- 詳細な相互作用が観察されました:水性ポケット内のアロマティックグループ,Mg2+またはアミノ酸残留と静電相互作用を形成するフォスフォナートグループ,そしてフォスミドミシン・フォスフォナート結合部位を占める硫酸.
結論:
- 決定された結晶構造は,ビスフォスフォナートのDXR.への結合に関する貴重な洞察を提供します.
- これらの発見は,強力なDXR阻害体としてのビスフォスフォネートおよび関連する化合物のさらなる開発を支持する.
- この研究は,ビスホスフォン酸塩ベースのDXR阻害剤が新型抗感染剤としての潜在力を強調しています.
さらに関連する動画
関連する概念動画
02:52Stereoisomerism
Isomerism in Complexes
Isomers are different chemical species that have the same chemical formula.
Transition metal complexes often exist as geometric isomers, in which the same atoms are connected through the same types of bonds but with differences in their orientation in space. Coordination complexes with two different ligands in the cis and trans positions from a ligand of interest form isomers. For example, the octahedral [Co(NH3)4Cl2]+ ion has two isomers (Figure 1) In the cis...
Isomers are different chemical species that have the same chemical formula.
Transition metal complexes often exist as geometric isomers, in which the same atoms are connected through the same types of bonds but with differences in their orientation in space. Coordination complexes with two different ligands in the cis and trans positions from a ligand of interest form isomers. For example, the octahedral [Co(NH3)4Cl2]+ ion has two isomers (Figure 1) In the cis...
01:57Gene Families
Gene families consist of groups of genes proposed to have originated from a common ancestor. Typically these arise through events in which a gene or genes are mistakenly duplicated during cell division. Unlike their parent genes (which are subject to selection pressure to maintain function), these gene copies do not need to preserve their sequences and may evolve at a relatively faster rate.
Occasionally these regions can be adapted to take on new roles within the organism, becoming novel genes...
Occasionally these regions can be adapted to take on new roles within the organism, becoming novel genes...
02:53Conservative Site-specific Recombination and Phase Variation
Because the DNA segments are cut and reorganized in a direction-specific manner, site-specific recombination has emerged as an efficient genetic engineering technique. Flippase and Cyclization recombinases or Flp and Cre, respectively, are two members of the tyrosine recombinase family derived from bacteriophages, that are used to mediate site-specific DNA insertions, deletions, and targeted expression of proteins in mammalian cell lines.
The recognition sites for Cre recombinase called LoxP...
The recognition sites for Cre recombinase called LoxP...
01:46Electron Transport Chain: Complex I and II
The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...
ROS generation is regulated and maintained at moderate levels necessary...
01:41The Supercomplexes in the Crista Membrane
The mitochondrial cristae membrane is the primary site for the oxidative phosphorylation (OXPHOS) process of energy conversion mediated through respiratory complexes I to V. These complexes have been widely studied for decades, and it has been proven that they form supramolecular structures called respiratory supercomplexes (SC). These higher-order complexes may be crucial in maintaining the biochemical structure and improving the physiological activity of the individual complexes while...
01:43Electron Transport Chain: Complex III and IV
During the electron transport chain, electrons from NADH and FADH2 are first transferred to complexes I and II, respectively. These two complexes then transfer the electrons to ubiquinol, which carries them further to complex III. Complex III passes the electrons across the intermembrane space to Cyt c, which carries them further to complex IV. Complex IV donates electrons to oxygen and reduces it to water. As electrons pass through complexes I, III, and IV, the energy released aids the pumping...