4E4D

Crystal structure of mouse RANKL-OPG complex

Summary for 4E4D

• Entry DOI: 10.2210/pdb4e4d/pdb
• Related: 1TNR 3ALQ 3K51 3ME2 3QBQ 3QO4
• Descriptor: Tumor necrosis factor ligand superfamily member 11, soluble form, Tumor necrosis factor receptor superfamily member 11B, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: tnf-related activation-induced cytokine-receptor, cysteine-rich domain, jelly-roll fold, cytokine-signaling protein complex, cytokine/signaling protein
• Biological source: Mus musculus (mouse); More
• Cellular location: Isoform 1: Cell membrane; Single-pass type II membrane protein. Isoform 2: Cell membrane; Single-pass type II membrane protein. Isoform 3: Cytoplasm. Tumor necrosis factor ligand superfamily member 11, soluble form: Secreted: O35235; Secreted: O08712
• Total number of polymer chains: 2
• Total formula weight: 37819.54

Authors

Nelson, C.A.,Fremont, D.H. (deposition date: 2012-03-12, release date: 2012-10-24, Last modification date: 2024-11-06)

Primary citation

Nelson, C.A.,Warren, J.T.,Wang, M.W.,Teitelbaum, S.L.,Fremont, D.H.
RANKL Employs Distinct Binding Modes to Engage RANK and the Osteoprotegerin Decoy Receptor.
Structure, 20:1971-1982, 2012

PubMed Abstract: Osteoprotegerin (OPG) and receptor activator of nuclear factor κB (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 ∼500-fold higher affinity than RANK and inhibits RANKL-stimulated osteoclastogenesis ∼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.

PubMed: 23039992
DOI: 10.1016/j.str.2012.08.030

Experimental method

X-RAY DIFFRACTION (2.7 Å)