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Sequence variation in ligand binding sites in proteins.

Thomas J Magliery1, Lynne Regan

  • 1Department of Molecular Biophysics & Biochemistry, Yale University, PO Box 208114, New Haven, CT 06520-8114, USA. magliery@chemistry.ohio-state.edu

BMC Bioinformatics
|October 1, 2005
PubMed
Summary

Sequence variation analysis reveals functionally important protein sites, even in poorly conserved regions. This method accurately predicts ligand binding sites in protein families like tetratricopeptide repeats (TPRs) and ankyrin repeats.

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Area of Science:

  • Bioinformatics
  • Computational Biology
  • Protein Science

Background:

  • Vast numbers of protein sequences are now available, but functionally important sites are often missed.
  • Poorly conserved protein regions are typically overlooked for functional significance.

Purpose of the Study:

  • To investigate the functional importance of poorly conserved protein sites.
  • To develop methods for identifying specificity-determining positions using sequence variation.

Main Methods:

  • Statistical analysis of sequence variation in protein families (TPRs, ankyrin repeats, Cys2His2 zinc fingers, PDZ domains).
  • Measuring sequence variation as deviation from a neutral reference state.
  • Utilizing probabilistic and information theory formalisms.

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Main Results:

  • Sequence variation analysis accurately identifies specificity-determining positions in multiple protein domains.
  • Highly variable sites correlate with positions in contact with peptide ligands.
  • Sequence 'hypervariation' alone can predict ligand binding sites in TPR and ankyrin repeat families.

Conclusions:

  • Sequence variation is a powerful tool for identifying functionally important residues, including in previously neglected regions.
  • The developed methods enhance the prediction of ligand binding sites.
  • This approach is particularly effective for protein families with diverse ligand binding profiles.