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Tightening the Recognition of Tetravalent Zr and Th Complexes by the Siderophore-Binding Mammalian Protein Siderocalin for Theranostic ApplicationsTightening the Recognition of Tetravalent Zr and Th Complexes by the Siderophore-Binding Mammalian Protein Siderocalin for Theranostic Applications
Structural highlights
FunctionNGAL_HUMAN Iron-trafficking protein involved in multiple processes such as apoptosis, innate immunity and renal development. Binds iron through association with 2,5-dihydroxybenzoic acid (2,5-DHBA), a siderophore that shares structural similarities with bacterial enterobactin, and delivers or removes iron from the cell, depending on the context. Iron-bound form (holo-24p3) is internalized following binding to the SLC22A17 (24p3R) receptor, leading to release of iron and subsequent increase of intracellular iron concentration. In contrast, association of the iron-free form (apo-24p3) with the SLC22A17 (24p3R) receptor is followed by association with an intracellular siderophore, iron chelation and iron transfer to the extracellular medium, thereby reducing intracellular iron concentration. Involved in apoptosis due to interleukin-3 (IL3) deprivation: iron-loaded form increases intracellular iron concentration without promoting apoptosis, while iron-free form decreases intracellular iron levels, inducing expression of the proapoptotic protein BCL2L11/BIM, resulting in apoptosis. Involved in innate immunity, possibly by sequestrating iron, leading to limit bacterial growth.[1] Publication Abstract from PubMedTargeted alpha 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 alpha-generating radioisotopes 225Ac and 227Th 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 beta110 = 29.65 +/- 0.65, 57.26 +/- 0.20, and 47.71 +/- 0.08, determined for the EuIII (a lanthanide surrogate for AcIII), ZrIV, and ThIV 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 ZrIV and ThIV. Finally, differences in biodistribution profiles between free and siderocalin-bound 238PuIV-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 225Ac and 227Th isotopes or to the positron emission tomography emitter 89Zr, independent of metal valence state. Engineered Recognition of Tetravalent Zirconium and Thorium by Chelator-Protein Systems: Toward Flexible Radiotherapy and Imaging Platforms.,Captain I, Deblonde GJ, Rupert PB, An DD, Illy MC, Rostan E, Ralston CY, Strong RK, Abergel RJ Inorg Chem. 2016 Nov 21;55(22):11930-11936. Epub 2016 Nov 1. PMID:27802058[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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