Engineering lanmodulin's selectivity for actinides over lanthanides by controlling solvent coordination and second-sphere interactions

Abstract

Developing chelators that combine high affinity and selectivity for lanthanides and/or actinides is paramount for numerous industries, including rare earths mining, nuclear waste management, and cancer medicine. In particular, achieving...

Radiolabeling and in vivo evaluation of lanmodulin with biomedically relevant lanthanide isotopes

“…[20][21][22] These apparent K d values represent the two tightest, cooperative metal-binding sites (EF-hands 2 and 3); EF-hand 1 is B4-fold weaker in the case of La 3+ , 20,23 and it is more susceptible to disruption by competing ligands. [23][24][25] The protein itself is stable under extreme pH and thermally challenging conditions. 20,26 LanM exhibits a large, cooperative, and highly selective conformational response to lanthanides that results in a shift from a disordered secondary structure to B60% alpha-helical character, a structure that retains the metal ions in their respective binding pockets with appropriate kinetic inertness.…”

“…22 Additionally, through modification of metal-binding site, LanM can be tuned to possess enhanced selectivity for actinides over lanthanides (Cm vs. Eu). 25 Based on the exceptional selectivity and resilience of LanM complexes with large lanthanides like La 3+ against physiological competing chelators such as phosphate, 20,22,26 achieved at biocompatible temperatures o40 1C, paired with stabilization of the metal-bound LanM species within a broad pH range, we hypothesized that the LanM protein could provide a suitable alternative to small molecular chelates with radiosensitive bifunctionalization handles for the radiolabeling and targeted delivery of biomedically relevant lanthanide isotopes. Herein, we demonstrate the endogenous and exogenous radiolabeling of LanM with 177 Lu (endogenous), 132/135 La (endogenous), and 89 Zr (exogenous), as well as the synthesis of [ 132/135 La]-LanM-PSMA, a LanM protein functionalized with a prostate cancer targeting peptide (Fig.…”

Lanthanides as Calcium Mimetic Species in Calcium-Signaling/Buffering Proteins: The Effect of Lanthanide Type on the Ca2+/Ln3+ Competition

“…Lanthanum (La 3+ ) and its fellow lanthanides (Ln 3+ ) have been extensively used to study the structure and biochemical properties of vast number of metalloproteins, the calcium-signaling/buffering proteins in particular [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. The latter (parvalbumin, calmodulin D, calcineurin, recoverin, troponin C, cadherin, and S100P) are involved in a plethora of physiological processes such as muscle contraction, vision, cell cycle regulation, brain cortex and cerebellum modulation, and microtubule organization [ 20 ].…”

A Novel Protein for the Bioremediation of Gadolinium Waste

“…Furthermore, we have recently developed a mutant of Methylobacterium [16]/ Methylorubrum extorquens AM1 that has acquired the ability of hyperaccumulating heavy lanthanides such as gadolinium [17] . The methylotrophic bacteria express a unique protein with the ability to bind lanthanides with picomolar affinity, termed lanmodulin[18, 19]. Lanmodulin binds lanthanides via EF-hand motifs that are 12 amino acids long[20].…”