Structural highlights
Function
[NGAL_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 PubMed
Boronic acids have long been known to form cyclic diesters with cis-diol compounds including many carbohydrates. This phenomenon was previously exploited to create an artificial lectin by incorporating l-p-boronophenylalanine (Bpa) into the ligand pocket of an engineered lipocalin, resulting in a so-called Borocalin. Here we describe the X-ray analysis of its covalent complex with 4-nitrocatechol as a high-affinity model ligand. As expected, the crystal structure reveals a cyclic diester between the biosynthetic boronate side chain and the two ortho-hydroxy substituents of the benzene ring. Interestingly, the boron also has a hydroxide ion associated, despite a just moderately basic pH 8.5 in the crystallization buffer. The complex is stabilized by a polar contact to the side chain of Asn134 within the ligand pocket, which validates the functional design of the Borocalin as an artificial sugar-binding protein. Our structural analysis demonstrates how a boronate can form a thermodynamically stable diester with a vicinal diol in a tetrahedral configuration in aqueous solution near physiological pH. Moreover, our data provide a basis for the further engineering of the Borocalin aiming at the specific recognition of biologically relevant glycans.
A tetrahedral boronic acid diester formed by a non-natural amino acid in the ligand pocket of an engineered lipocalin.,Sommer CA, Eichinger A, Skerra A Chembiochem. 2019 Aug 7. doi: 10.1002/cbic.201900405. PMID:31390134[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Yang J, Goetz D, Li JY, Wang W, Mori K, Setlik D, Du T, Erdjument-Bromage H, Tempst P, Strong R, Barasch J. An iron delivery pathway mediated by a lipocalin. Mol Cell. 2002 Nov;10(5):1045-56. PMID:12453413
- ↑ Sommer CA, Eichinger A, Skerra A. A tetrahedral boronic acid diester formed by a non-natural amino acid in the ligand pocket of an engineered lipocalin. Chembiochem. 2019 Aug 7. doi: 10.1002/cbic.201900405. PMID:31390134 doi:http://dx.doi.org/10.1002/cbic.201900405
