9CEQ

Lanthanide Binding Tag complex LBT3-NH2:La3+

Summary for 9CEQ

• Entry DOI: 10.2210/pdb9ceq/pdb
• NMR Information: BMRB: 31181
• Descriptor: Lanthanide Binding Tag Peptide, LANTHANUM (III) ION (2 entities in total)
• Functional Keywords: rare earth complex, calmodulin derivative, de novo protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 2058.93

Authors

Kt, S.,Messinger, R.J.,Favaro, D.C. (deposition date: 2024-06-27, release date: 2024-07-17, Last modification date: 2025-06-04)

Primary citation

Kt, S.S.,Qiao, B.,Marmorstein, J.G.,Wang, Y.,Favaro, D.C.,Stebe, K.J.,Petersson, E.J.,Radhakrishnan, R.,de la Fuente-Nunez, C.,Tu, R.S.,Maldarelli, C.,Olvera de la Cruz, M.,Messinger, R.J.
The Role of Asparagine as a Gatekeeper Residue in the Selective Binding of Rare Earth Elements by Lanthanide-Binding Peptides.
Chemistry, :e202501318-e202501318, 2025

PubMed Abstract: Lanthanide-binding tag (LBT) peptides selectively complex lanthanide cations (Ln) in their binding pockets and are promising for lanthanide separation. However, designing LBTs that selectively target specific Ln cations remains a challenge due to limited molecular-level understanding and control of interactions within the lanthanide-binding pocket. In this study, we reveal that the N5 asparagine residue acts as a gatekeeper in the binding pocket, resulting in a 100-fold selectivity for smaller Lu over larger La cations. Nuclear magnetic resonance spectroscopy and molecular dynamics simulations show that the N5 residue weakly binds to the larger La cation, permitting HO molecules inside the pocket. For the smaller Lu cations, the N5 residue forms an inter-arm hydrogen bond with the E14 glutamic acid residue, locking the Lu cation in the pocket and preventing HO infiltration. Mutating the N5 asparagine to a D5 aspartic acid prevents such a hydrogen bond, eliminating the gatekeeping mechanism and precipitously reducing selectivity. The resulting binding affinity to Ln cations is non-monotonic but generally increases with cation size. These results suggest a molecular design paradigm: the reduced affinity for larger lanthanides is due to open pocket conformations, while the selectivity of smaller Ln cations over larger ones is due to the gatekeeping hydrogen bond.

PubMed: 40312258
DOI: 10.1002/chem.202501318

Experimental method

SOLUTION NMR