Structure-function of the TNF receptor-like cysteine-rich domain of osteoprotegerin.
Osteoprotegerin (OPG) is a soluble decoy receptor that inhibits osteoclastogenesis and is closely associated with bone resorption processes. We have designed and determined the solution structures of potent OPG analogue peptides, derived from sequences of the cysteine-rich domain of OPG. The inhibitory effects of the peptides on osteoclastogenesis are dose-dependent (10(-6) M-10(-4) M), and the activity of the linear peptide at 10(-4) M is ten-fold higher than that of the cyclic OPG peptide. Both linear and cyclic peptides have a beta-turn-like conformation and the cyclic peptide has a rigid conformation, suggesting that structural flexibility is an important factor for receptor binding. Based on structural and biochemical information about RANKL and the OPG peptides, we suggest that complex formation between the peptide and RANKL is mediated by both hydrophobic and hydrogen bonding interactions. These results provide structural insights that should aid in the design of peptidyl-mimetic inhibitors for treating metabolic bone diseases caused by abnormal osteoclast recruitment.
Shin
Joon
J
Department of Biochemistry and Protein Network Research Center, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea.
Kim
Young-Mee
YM
Li
Song-Zhe
SZ
Lim
Sung-Kil
SK
Lee
Weontae
W
D000818:Animals; D002478:Cells, Cultured; D003545:Cysteine / Q000032:analysis; D016173:Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors; D051379:Mice; D019906:Nuclear Magnetic Resonance, Biomolecular; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D053244:Osteoprotegerin / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D053245:RANK Ligand / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
D053244:Osteoprotegerin; D010455:Peptides; D053245:RANK Ligand; D016173:Macrophage Colony-Stimulating Factor; D003545:Cysteine