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1. Modulating metal-centered dimerization of a lanthanide chaperone protein for separation of light lanthanides

   https://doi.org/10.1073/pnas.2410926121  

   Larrinaga, Wyatt B; Jung, Jonathan J; Lin, Chi-Yun; Boal, Amie K; Cotruvo_Jr, Joseph A (October 2024, Proceedings of the National Academy of Sciences)

   Elucidating details of biology’s selective uptake and trafficking of rare earth elements, particularly the lanthanides, has the potential to inspire sustainable biomolecular separations of these essential metals for myriad modern technologies. Here, we biochemically and structurally characterizeMethylobacterium(Methylorubrum)extorquensLanD, a periplasmic protein from a bacterial gene cluster for lanthanide uptake. This protein provides only four ligands at its surface-exposed lanthanide-binding site, allowing for metal-centered protein dimerization that favors the largest lanthanide, La^III. However, the monomer prefers Nd^IIIand Sm^III, which are disfavored lanthanides for cellular utilization. Structure-guided mutagenesis of a metal-ligand and an outer-sphere residue weakens metal binding to the LanD monomer and enhances dimerization for Pr^IIIand Nd^IIIby 100-fold. Selective dimerization enriches high-value Pr^IIIand Nd^IIIrelative to low-value La^IIIand Ce^IIIin an all-aqueous process, achieving higher separation factors than lanmodulins and comparable or better separation factors than common industrial extractants. Finally, we show that LanD interacts with lanmodulin (LanM), a previously characterized periplasmic protein that shares LanD’s preference for Nd^IIIand Sm^III. Our results suggest that LanD’s unusual metal-binding site transfers less-desirable lanthanides to LanM to siphon them away from the pathway for cytosolic import. The properties of LanD show how relatively weak chelators can achieve high selectivity, and they form the basis for the design of protein dimers for separation of adjacent lanthanide pairs and other metal ions. 

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2. Lanthanide-dependent coordination interactions in lanmodulin: a 2D IR and molecular dynamics simulations study

   https://doi.org/10.1039/D1CP03628A  

   Liu, Stephanie; Featherston, Emily R.; Cotruvo, Joseph A.; Baiz, Carlos R. (October 2021, Physical Chemistry Chemical Physics)

   The biological importance of lanthanides, and the early lanthanides (La 3+ –Nd 3+ ) in particular, has only recently been recognized, and the structural principles underlying selective binding of lanthanide ions in biology are not yet well established. Lanmodulin (LanM) is a novel protein that displays unprecedented affinity and selectivity for lanthanides over most other metal ions, with an uncommon preference for the early lanthanides. Its utilization of EF-hand motifs to bind lanthanides, rather than the Ca 2+ typically recognized by these motifs in other proteins, has led it to be used as a model system to understand selective lanthanide recognition. Two-dimensional infrared (2D IR) spectroscopy combined with molecular dynamics simulations were used to investigate LanM's selectivity mechanisms by characterizing local binding site geometries upon coordination of early and late lanthanides as well as calcium. These studies focused on the protein's uniquely conserved proline residues in the second position of each EF-hand binding loop. We found that these prolines constrain the EF-hands for strong coordination of early lanthanides. Substitution of this proline results in a more flexible binding site to accommodate a larger range of ions but also results in less compact coordination geometries and greater disorder within the binding site. Finally, we identify the conserved glycine in the sixth position of each EF-hand as a mediator of local binding site conformation and global secondary structure. Uncovering fundamental structure–function relationships in LanM informs the development of synthetic biology technologies targeting lanthanides in industrial applications. 

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3. Comprehensive structural study of lanthanide(III) chloride hydrates: [ RE Cl ₃ · x H ₂ O ( RE = La–Nd, Sm–Lu; x = 6, 7)]

   https://doi.org/10.1107/S2056989024011319  

   Kandabadage, Thimira; Legnon, Beau; Baranets, Sviatoslav (December 2024, Acta Crystallographica Section E Crystallographic Communications)

   A comprehensive crystallographic study is presented of the complete series of rare-earth(III) chloride hydrates. Early lanthanides form dimeric [(H₂O)₇RE(μ-Cl)₂RE(H₂O)₇]⁴⁺binuclear complexes in which eachREatom (RE= La³⁺, Ce³⁺) is coordinated by seven H₂O molecules and two bridging inner-sphere chloride ions. Di-μ-chlorido-bis[heptaaqualanthanide(III)] tetrachloride, [(H₂O)₇RE(μ-Cl)₂RE(H₂O)₇]Cl₄, crystallizes in the triclinic space groupP1. Heavier lanthanides exhibit monomeric [RECl₂(H₂O)₆]⁺units where eachREatom (RE= Pr³⁺, Nd³⁺, Sm³⁺–Lu³⁺) is coordinated by six H₂O molecules and two inner-sphere chloride ions. Hexaaquadichloridolanthanide(III) chlorides, [RECl₂(H₂O)₆]Cl, adopt the monoclinic space groupP2/c.In both structures, the cationicinner-spherecomplex is counter-charged by the corresponding number ofouter-sphereCl⁻anions, in which the metal ion and outer-sphere chloride ion lie on crystallographic twofold axes. Crystal structures for all compounds were determined in high quality with refined H-atom positions and were collected at the same temperature (100 K), providing a uniform structural dataset and addressing discrepancies in previous reports. The crystal structure of [HoCl₂(H₂O)₆]Cl is reported for the first time. 

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4. Lanthanide‐Controlled Protein Switches: Development and In Vitro and In Vivo Applications

   https://doi.org/10.1002/anie.202411584  

   Guo, Zhong; Smutok, Oleh; Ronacher, Chantal; Aguiar_Rocha, Raquel; Walden, Patricia; Mureev, Sergey; Cui, Zhenling; Katz, Evgeny; Scott, Colin; Alexandrov, Kirill (February 2025, Angewandte Chemie International Edition)

   Abstract Lanthanides, which are part of the rare earth elements group have numerous applications in electronics, medicine and energy storage. However, our ability to extract them is not meeting the rapidly increasing demand. The discovery of the bacterial periplasmic lanthanide‐binding protein lanmodulin spurred significant interest in developing biotechnological routes for lanthanide detection and extraction. Here we report the construction of β‐lactamase‐lanmodulin chimeras that function as lanthanide‐controlled enzymatic switches. Optimized switches demonstrated dynamic ranges approaching 3000‐fold and could accurately quantify lanthanide ions in simple colorimetric or electrochemical assays.E.colicells expressing such chimeras grow on β‐lactam antibiotics only in the presence of lanthanide ions. The developed lanthanide‐controlled protein switches represent a novel platform for engineering metal‐binding proteins for biosensing and microbial engineering. 

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5. Lanthanide extraction selectivity of a tripodal carbamoylmethylphosphine oxide ligand system

   https://doi.org/10.1039/c8dt02239a  

   Patterson, Michael G.; Mulville, Andrew K.; Connor, Emily K.; Henry, Alyssa T.; Hudson, Michael L.; Tissue, Kirsten; Biros, Shannon M.; Werner, Eric J. (October 2018, Dalton Transactions)

   Four tripodal carbamoylmethylphosphine oxide (CMPO)-based ligands are reported here and assessed with regard to lanthanide (Ln) coordination chemistry and selective extraction of lanthanide ions from aqueous solution. Inspired by previous liquid–liquid extraction studies that suggested a preference for terbium( iii ), the current work further probes the extraction behavior of a tris-(2-aminoethyl)amine (TREN) capped, ethoxy substituted CMPO ligand with respect to the entire series of lanthanides. Upon confirmation of Tb 3+ extraction selectivity versus the whole series, experiments were conducted to assess the effect of increasing the alkyl chain length within the ligand TREN cap, as well as changing the CMPO substituents by replacing the ethoxy groups with more hydrophobic phenyl groups to promote solubility in the organic extraction solvent. Extraction efficiencies remained low for most lanthanides upon increasing the cap size, with % E values consistently around 5%, and a complete loss of Tb 3+ preference was noted with a decrease in % E from 18% to 3.5%. For the agent employing the original, smaller TREN cap but with phenyl substituents on the CMPO units, an increase in extraction toward the middle of the row was again observed, albeit modest, with relatively high % E values for both Gd 3+ and Tb 3+ versus the other lanthanides (13 and 11%, respectively). A more dramatic extraction selectivity for the phenyl substituted ligand was achieved upon modification of the ligand to metal ratio, with a 100 : 1 ratio resulting in a near linear decrease in % E from 41% for La 3+ to 3.7% for Lu 3+ . Finally, modification of the TREN capping scaffold by adding an oxygen atom to the central nitrogen led to consistently low % E values, revealing the effect of TREN cap oxidation on Ln extraction for this tripodal CMPO ligand system. 

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