Crystal structure of the TRANCE/RANKL cytokine reveals determinants of receptor-ligand specificity

RANK, the receptor activator of NF-kappaB, and its ligand RANKL (initially termed TRANCE, also termed ODF and OPGL), are a TNF superfamily receptor-li gand pair that govern the development and function of osteoclasts, lymphoid tissue, and mammary epithelium. While TNF family cytokines share a common structural scaffold, individual receptor-ligand pairs associate with high s pecificity. Given the low level of amino acid conservation among members of the TNF superfamily, the means by which these molecules achieve specificit y cannot be completely understood without knowledge of their three-dimensio nal structures. To determine the elements of RANKL that mediate RANK activa tion, we have crystallized the ectodomain of murine RANKL and solved its st ructure to a resolution of 2.6 Angstrom. RANKL self-associates as a homotri mer with four unique surface loops that distinguish it from other TNF famil y cytokines. Mutagenesis of selected residues in these loops significantly modulates RANK activation, as evidenced by in vitro osteoclastogenesis, the reby establishing their necessity in mediating the biological activities of RANKL Such structural determinants of RANKL-RANK specificity may be of rel evance in the pharmacologic design of compounds to ameliorate osteopenic di sorders of bone.