BoneKEy Reports | BoneKEy Watch

How RANKL binds to RANK, and how OPG acts as 'decoy'

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DOI:10.1038/bonekey.2012.147

Luan et al. present data on the three-dimensional interaction between the receptor activator of the NF-kB ligand (RANKL), RANK, its signaling receptor, and osteoprotegerin (OPG), which blocks interactions between RANKL and RANK.

The researchers determined the crystal structure of the human RANKL trimer when bound to the N-terminal fragment of human OPG. This revealed that the RANKL trimer nestles into three grooves created by the symmetrical alignment of three monomers of the OPG N-terminal fragment. Each fragment contains four cysteine-rich domains (CRDs) that are homologous with the tumor necrosis factor receptor (TNFR). Binding is further enhanced by a loop from one of the OPG-CRDs, which fits into a shallow groove in the RANKL molecule.

OPG is regarded as a decoy receptor for RANKL; these observations show that it is able to do so by directly blocking the active binding sites between RANKL and RANK. The findings suggest there may be therapeutic potential in designing small molecules that target this interaction by fitting into vital hotspots within the binding sites identified.

Editor's comment: Although full-size OPGs with C-terminal regions form dimers and show stronger inhibitory activity against RANKL than monomers, the information obtained in this study may provide new clues for developing small molecules that regulate RANKL binding to RANK.

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