5KID

Tightening the Recognition of Tetravalent Zr and Th Complexes by the Siderophore-Binding Mammalian Protein Siderocalin for Theranostic Applications

5KID の概要

• エントリーDOI: 10.2210/pdb5kid/pdb
• 関連するPDBエントリー: 5KHP
• 分子名称: Neutrophil gelatinase-associated lipocalin, THORIUM ION, N,N'-(butane-1,4-diyl)bis(N-{3-[(2,3-dihydroxybenzene-1-carbonyl)amino]propyl}-2,3-dihydroxybenzamide), ... (7 entities in total)
• 機能のキーワード: siderophore-binding, ngal, metal binding protein
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Secreted : P80188
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 65581.37

構造登録者

Rupert, P.B.,Strong, R.K. (登録日: 2016-06-16, 公開日: 2017-04-26, 最終更新日: 2024-11-06)

主引用文献

Captain, I.,Deblonde, G.J.,Rupert, P.B.,An, D.D.,Illy, M.C.,Rostan, E.,Ralston, C.Y.,Strong, R.K.,Abergel, R.J.
Engineered Recognition of Tetravalent Zirconium and Thorium by Chelator-Protein Systems: Toward Flexible Radiotherapy and Imaging Platforms.
Inorg Chem, 55:11930-11936, 2016

PubMed Abstract: Targeted α therapy holds tremendous potential as a cancer treatment: it offers the possibility of delivering a highly cytotoxic dose to targeted cells while minimizing damage to surrounding healthy tissue. The metallic α-generating radioisotopes Ac and Th are promising radionuclides for therapeutic use, provided adequate chelation and targeting. Here we demonstrate a new chelating platform composed of a multidentate high-affinity oxygen-donating ligand 3,4,3-LI(CAM) bound to the mammalian protein siderocalin. Respective stability constants log β = 29.65 ± 0.65, 57.26 ± 0.20, and 47.71 ± 0.08, determined for the Eu (a lanthanide surrogate for Ac), Zr, and Th complexes of 3,4,3-LI(CAM) through spectrophotometric titrations, reveal this ligand to be one of the most powerful chelators for both trivalent and tetravalent metal ions at physiological pH. The resulting metal-ligand complexes are also recognized with extremely high affinity by the siderophore-binding protein siderocalin, with dissociation constants below 40 nM and tight electrostatic interactions, as evidenced by X-ray structures of the protein:ligand:metal adducts with Zr and Th. Finally, differences in biodistribution profiles between free and siderocalin-bound Pu-3,4,3-LI(CAM) complexes confirm in vivo stability of the protein construct. The siderocalin:3,4,3-LI(CAM) assembly can therefore serve as a "lock" to consolidate binding to the therapeutic Ac and Th isotopes or to the positron emission tomography emitter Zr, independent of metal valence state.

PubMed: 27802058
DOI: 10.1021/acs.inorgchem.6b02041

実験手法

X-RAY DIFFRACTION (2.15 Å)