Design of a RANK-Mimetic Peptide Inhibitor of Osteoclastogenesis with Enhanced RANKL-Binding Affinity

  • Hur, Jeonghwan (Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine) ;
  • Ghosh, Ambarnil (Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine) ;
  • Kim, Kabsun (Department of Pharmacology, Chonnam National University Medical School) ;
  • Ta, Hai Minh (Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine) ;
  • Kim, Hyunju (Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine) ;
  • Kim, Nacksung (Department of Pharmacology, Chonnam National University Medical School) ;
  • Hwang, Hye-Yeon (Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine) ;
  • Kim, Kyeong Kyu (Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine)
  • Received : 2015.10.20
  • Accepted : 2016.01.26
  • Published : 2016.04.30


The receptor activator of nuclear factor ${\kappa}B$ (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.


bone resorption;docking;molecular dynamics simulation;peptide inhibitor;receptor activator of nuclear factor-${\kappa}B$ (RANK);structure


Grant : BK21플러스

Supported by : 전남대학교


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