Research ArticlePharmacology

Manipulation of receptor oligomerization as a strategy to inhibit signaling by TNF superfamily members

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Science Signaling  19 Aug 2014:
Vol. 7, Issue 339, pp. ra80
DOI: 10.1126/scisignal.2004948

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An Inhibitor Breaks RANK

The cytokine receptor activator of nuclear factor κB ligand (RANKL) promotes the resorption of bone by osteoclasts; however, excessive activation of the RANKL receptor RANK leads to pathological bone loss. RANKL exists as a trimer composed of three subunits, which engage three receptor subunits to activate signaling (see the Perspective by Ou-Yang and Siegel). Warren et al. generated a form of RANKL in which the three subunits were tethered to each other by linkers. Two of the subunits were mutated to increase their affinity for RANK, whereas the third subunit had mutations that prevented receptor binding. This engineered RANKL variant bound to RANK but prevented productive engagement of all three receptor subunits and blocked osteoclast function in mice. This strategy might be applicable to other members of the tumor necrosis factor family to generate specific inhibitors.