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Structural and dynamic characterization of human Wnt2-Fzd7 complex using computational approaches

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Abstract

Wnt and Frizzled (Fzd) family members play crucial roles in the self-renewal of tumor-initiating cells. Until now, only a few studies have addressed the distinct mechanism of Wnt–Fzd interactions. In this study, we suggest a possible interaction mode of Wnt2 with the Fzd7 cysteine-rich domain (CRD)—both of which are up-regulated in some types of cancer. A combination of homology modeling, molecular docking and molecular dynamics (MD) simulations was carried out to study this ligand–receptor complex in great detail. The results demonstrated the unique dynamic behavior of Wnt2 upon binding to Fzd7. Interestingly, the β-strand content of the C-terminal binding site of Wnt2 was obviously reduced when bound to Fzd7 CRD. Moreover, the N-terminal and C-terminal binding sites of Wnt2 appeared to interact with the C-terminal and N-terminal binding sites of Fzd7, respectively. Calculation of the binding energies uncovered the pivotal role of electrostatic and hydrophobic interactions in the binding of Wnt2 to Fzd7 CRD. In conclusion, this study provides valuable insights into the mechanism of the Wnt2-Fzd7 CRD interaction for application in colorectal cancer prevention programs.

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Abbreviations

3D:

Three dimensional

CN:

Cluster number

CRC:

Colorectal cancer

CRD:

Cysteine-rich domain

CTD:

C-terminal domain

DKK:

Dikpoff

DOPE:

Discrete optimized potential energy

FZD:

Frizzled

HM:

Homology modeling

LRP:

Lipoprotein receptor related protein

LE:

Lowest energy

mFZD:

mouse frizzled

MD:

Molecular dynamics

NTD:

N-terminal domain

PDB:

Protein Data Bank

Pdf:

Probability density function

Rg:

Radius of gyration

RMSD:

Root mean square deviation

RMSF:

Root mean square fluctuations

SASA:

Solvent accessible surface area

SPC:

Simple point charge

TCF:

Transcription cell factor

Wnt:

Wingless Int

xWNT:

Xenopus Wnt

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Acknowledgments

This study was supported by the Semnan University of Medical Sciences (Grant Number: 810) and the Pasteur Institute of Iran (Grant Number: 94/0110/15866).

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Authors and Affiliations

  1. Department and Biotechnology Research Center, Semnan University of Medical Sciences, Semnan, Iran

    Hourieh Kalhor, Ali Akbar Shabani & Mohammad Reza Akbari Eidgahi

  2. Molecular Medicine Department, Pasteur Institute of Iran, Tehran, Iran

    Hourieh Kalhor, Mansour Poorebrahim, Hamzeh Rahimi, Morteza Karimipoor & Ladan Teimoori-Toolabi

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  1. Hourieh Kalhor
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Correspondence to Mohammad Reza Akbari Eidgahi or Ladan Teimoori-Toolabi.

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Kalhor, H., Poorebrahim, M., Rahimi, H. et al. Structural and dynamic characterization of human Wnt2-Fzd7 complex using computational approaches. J Mol Model 24, 274 (2018). https://doi.org/10.1007/s00894-018-3788-3

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