4e4d
Crystal structure of mouse RANKL-OPG complex
Structural highlights
DiseaseTNF11_MOUSE Note=Deficiency in Tnfsf11 results in failure to form lobulo-alveolar mammary structures during pregnancy, resulting in death of newborns. Trance-deficient mice show severe osteopetrosis, with no osteoclasts, marrow spaces, or tooth eruption, and exhibit profound growth retardation at several skeletal sites, including the limbs, skull, and vertebrae and have marked chondrodysplasia, with thick, irregular growth plates and a relative increase in hypertrophic chondrocytes. FunctionTNF11_MOUSE Cytokine that binds to TNFRSF11B/OPG and to TNFRSF11A/RANK. Osteoclast differentiation and activation factor. Augments the ability of dendritic cells to stimulate naive T-cell proliferation. May be an important regulator of interactions between T-cells and dendritic cells and may play a role in the regulation of the T-cell-dependent immune response. May also play an important role in enhanced bone-resorption in humoral hypercalcemia of malignancy. Publication Abstract from PubMedOsteoprotegerin (OPG) and receptor activator of nuclear factor kappaB (RANK) are members of the tumor necrosis factor receptor (TNFR) superfamily that regulate osteoclast formation and function by competing for RANK ligand (RANKL). RANKL promotes osteoclast development through RANK activation, while OPG inhibits this process by sequestering RANKL. For comparison, we solved crystal structures of RANKL with RANK and RANKL with OPG. Complementary biochemical and functional studies reveal that the monomeric cytokine-binding region of OPG binds RANKL with approximately 500-fold higher affinity than RANK and inhibits RANKL-stimulated osteoclastogenesis approximately 150 times more effectively, in part because the binding cleft of RANKL makes unique contacts with OPG. Several side chains as well as the C-D and D-E loops of RANKL occupy different orientations when bound to OPG versus RANK. High affinity OPG binding requires a 90s loop Phe residue that is mutated in juvenile Paget's disease. These results suggest cytokine plasticity may help to fine-tune specific tumor necrosis factor (TNF)-family cytokine/receptor pair selectivity. RANKL Employs Distinct Binding Modes to Engage RANK and the Osteoprotegerin Decoy Receptor.,Nelson CA, Warren JT, Wang MW, Teitelbaum SL, Fremont DH Structure. 2012 Oct 2. pii: S0969-2126(12)00334-6. doi:, 10.1016/j.str.2012.08.030. PMID:23039992[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also
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