Ligand Preference Inferred from the Structure of Neutrophil Gelatinase Associated Lipocalin

Abstract

Neutrophil gelatinase associated lipocalin (NGAL), a constituent of neutrophil granules, is a member of the lipocalin family of binding proteins. NGAL can also be highly induced in epithelial cells in both inflammatory and neoplastic colorectal disease. NGAL is proposed to mediate inflammatory responses by sequestering neutrophil chemoattractants, particularly N-formylated tripeptides and possibly leukotriene B(4) and platelet activating factor. The crystal structures of NGAL display a typical lipocalin fold, albeit with an unusually large and atypically polar binding site, or calyx. The fold of NGAL is most similar to the epididymal retinoic acid-binding protein, another lipocalin, though the overall architecture of the calyces are very different. The crystal structures also reveal either sulfate ions or an adventitiously copurified fatty acid bound in the binding site. Neither ligand is displaced by added N-formylated tripeptides. The size, shape, and character of the NGAL calyx, as well as the low relative affinity for N-formylated tripeptides, suggest that neither the copurified fatty acid nor any of the proposed ligands are likely to be the preferred ligand of this protein. Comparisons between the crystal structures and the recently reported solution structure of NGAL reveal significant differences, in terms of both the details of the structure and the overall flexibility of the fold.

The pathogen-associated iroA gene cluster mediates bacterial evasion of lipocalin 2

“…Structural analyses of siderophore-binding by Lcn2 (4,19,20) demonstrate significant steric clashes between even a single modeled glucose adduct on Ent in any of the catechol-binding pockets in the Lcn2 calyx ( Fig. 2A).…”

Neutrophil Gelatinase‐Associated Lipocalin as a Biomarker of Allograft Function After Renal Transplantation: Evaluation of the Current Status and Future Insights

“…Professor Strong defined lipocalins as “small proteins that cells send out to bind things and carry them back” 14. Successive studies proved the ability of NGAL to bind with high affinity bacterial siderophores or endogenous compounds in mammals 15, 16, its key role in iron transport into cells, and iron‐mediated downstream cellular responses 17, 18.…”

Enterobactin: An archetype for microbial iron transport

“…Recently, neutrophil gelatinase-associated lipocalin [NGAL, also called superinducible protein 24 (SIP24), 24p3, neu-related lipocalin (NRL0), and uterocalin] has been proposed as an antibacterial component of the innate immune system (67). NGAL is a human protein secreted by neutrophils (68,69) and epithelial cells during inf lammation and rapid cell growth (70). NGAL, like most lipocalins, is thought to modulate cellular processes by binding to specific cell-surface sites or receptors (71).…”