Unlike the high affinity LDL receptors that bind to LDL particles and internalize them for degradation and clearance, LRP1 binds to multiple ligands but more specifically to aggregated LDL (AgLDL) [88], [91].
RAGE binds multiple structurally diverse ligands and is considered a pattern recognition receptor, but the structural basis for RAGE binding to multiple ligands is not well understood.
Myriad interactions in nature use polyvalent binding, where multiple ligands on one entity bind to multiple receptors on another: antibody antigen interactions, virus−cell binding, cell cell signaling, and others.
In addition, ligands can bind to multiple receptor and/or co-receptor combinations to stimulate different downstream target gene expression.
RAGE binds to multiple families of ligands, such as advanced glycation end products (AGEs), S100s, and amphoterin, and plays a key role in diabetes, inflammation, and cancer [5], [10].
Experimental determination of atomic resolution structures of ligands weakly bound to multiple binding sites is often challenging.
The need for "balanced" signaling provides an explanation for how a signaling system in which a single ligand binds to multiple receptor subtypes may develop naturally, although some of these active downstream pathways have diametrically opposite cellular effects [ 17].
On the other hand, the ability to bind multiple ligands at a given site is largely derived from hinge-based motions.
Megalin has been shown to bind and internalize multiple ligands, including the soluble folate binding protein (Folr1), and sonic hedgehog (Shh), among others [ 19, 25- 29].
