Homology modeling of the DNA-binding domain of human Smad5: a molecular model for inhibitor design

J Mol Graph Model. 2006 Jan;24(4):271-7. doi: 10.1016/j.jmgm.2005.09.009. Epub 2005 Oct 21.

Abstract

Members of the Smad protein family function as signal transducers of the transforming growth factor (TGF-beta) superfamily proteins. The human Smad5 protein, a signal transducer downstream of TGF-beta/BMP receptors, is composed of N-terminal DNA binding domain (MH1) and C-terminal protein-protein interaction domain (MH2) connected together by a linker motif. We used homology-modeling techniques to generate a reliable molecular model of the Smad5 MH1 domain based on the crystal structure of Smad3 MH1 domain. Our study presents the structural features of a BMP-regulated, R-Smad subfamily member (consisting of Smad1, Smad5 and Smad8) for the first time. This model provides a structural basis for explaining both functional similarities and differences between Smad3 and Smad5. Also, the structural model of this molecular target would be useful for structure-based inhibitor design because of its high accuracy. The results of our study provide important insights into understanding the structure-function relationship of the members of the Smad protein family and can serve to guide future genetic and biochemical experiments in this area.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Conserved Sequence
  • DNA / metabolism*
  • Drug Design*
  • Humans
  • Models, Molecular*
  • Molecular Sequence Data
  • Phylogeny
  • Protein Structure, Tertiary
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Smad5 Protein / antagonists & inhibitors*
  • Smad5 Protein / chemistry*
  • Smad5 Protein / genetics
  • Smad5 Protein / metabolism

Substances

  • Smad5 Protein
  • DNA