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Mol. Cells 2008; 25(3): 352-357

Published online May 31, 2008

© The Korean Society for Molecular and Cellular Biology

Structure-Function of the TNF Receptor-like Cysteine-rich Domain of Osteoprotegerin

Joon Shin, Young-Mee Kim, Song-Zhe Li, Sung-Kil Lim and Weontae Lee

Abstract

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 β-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.

Keywords Bone Disease, NMR, OPG Analogue Peptides, Osteoprotegerin

Article

Research Article

Mol. Cells 2008; 25(3): 352-357

Published online May 31, 2008

Copyright © The Korean Society for Molecular and Cellular Biology.

Structure-Function of the TNF Receptor-like Cysteine-rich Domain of Osteoprotegerin

Joon Shin, Young-Mee Kim, Song-Zhe Li, Sung-Kil Lim and Weontae Lee

Abstract

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 β-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.

Keywords: Bone Disease, NMR, OPG Analogue Peptides, Osteoprotegerin

Mol. Cells
Sep 30, 2022 Vol.45 No.9, pp. 603~672
COVER PICTURE
The Target of Rapamycin Complex (TORC) is a central regulatory hub in eukaryotes, which is well conserved in diverse plant species, including tomato (Solanum lycopersicum). Inhibition of TORC genes (SlTOR, SlLST8, and SlRAPTOR) by VIGS (virus-induced gene silencing) results in early fruit ripening in tomato. The red/ orange tomatoes are early-ripened TORC-silenced fruits, while the green tomato is a control fruit. Top, left, control fruit (TRV2-myc); top, right, TRV2-SlLST8; bottom, left, TRV2-SlTOR; bottom, right, TRV2-SlRAPTOR(Choi et al., pp. 660-672).

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