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Design of a RANK-Mimetic Peptide Inhibitor of Osteoclastogenesis with Enhanced RANKL-Binding Affinity
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  • Journal title : Molecules and Cells
  • Volume 39, Issue 4,  2016, pp.316-321
  • Publisher : Korea Society for Molecular and Cellular Biology
  • DOI : 10.14348/molcells.2016.2286
 Title & Authors
Design of a RANK-Mimetic Peptide Inhibitor of Osteoclastogenesis with Enhanced RANKL-Binding Affinity
Hur, Jeonghwan; Ghosh, Ambarnil; Kim, Kabsun; Ta, Hai Minh; Kim, Hyunju; Kim, Nacksung; Hwang, Hye-Yeon; Kim, Kyeong Kyu;
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 Abstract
The receptor activator of nuclear factor (RANK) and its ligand RANKL are key regulators of osteoclastogenesis and well-recognized targets in developing treatments for bone disorders associated with excessive bone resorption, such as osteoporosis. Our previous work on the structure of the RANK-RANKL complex revealed that Loop3 of RANK, specifically the non-canonical disulfide bond at the tip, performs a crucial role in specific recognition of RANKL. It also demonstrated that peptide mimics of Loop3 were capable of interfering with the function of RANKL in osteoclastogenesis. Here, we reported the structure-based design of a smaller peptide with enhanced inhibitory efficiency. The kinetic analysis and osteoclast differentiation assay showed that in addition to the sharp turn induced by the disulfide bond, two consecutive arginine residues were also important for binding to RANKL and inhibiting osteoclastogenesis. Docking and molecular dynamics simulations proposed the binding mode of the peptide to the RANKL trimer, showing that the arginine residues provide electrostatic interactions with RANKL and contribute to stabilizing the complex. These findings provided useful information for the rational design of therapeutics for bone diseases associated with RANK/RANKL function.
 Keywords
bone resorption;docking;molecular dynamics simulation;peptide inhibitor;receptor activator of nuclear factor- (RANK);structure;
 Language
English
 Cited by
1.
Unraveling Binding Interactions between Human RANKL and Its Decoy Receptor Osteoprotegerin, The Journal of Physical Chemistry B, 2017  crossref(new windwow)
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