A polypeptide "building block" for the β-trefoil fold identified by "top-down symmetric deconstruction"

J Mol Biol. 2011 Apr 15;407(5):744-63. doi: 10.1016/j.jmb.2011.02.002. Epub 2011 Feb 16.


Fibroblast growth factor-1, a member of the 3-fold symmetric β-trefoil fold, was subjected to a series of symmetric constraint mutations in a process termed "top-down symmetric deconstruction." The mutations enforced a cumulative exact 3-fold symmetry upon symmetrically equivalent positions within the protein and were combined with a stability screen. This process culminated in a β-trefoil protein with exact 3-fold primary-structure symmetry that exhibited excellent folding and stability properties. Subsequent fragmentation of the repeating primary-structure motif yielded a 42-residue polypeptide capable of spontaneous assembly as a homotrimer, producing a thermostable β-trefoil architecture. The results show that despite pronounced reduction in sequence complexity, pure symmetry in the design of a foldable, thermostable β-trefoil fold is possible. The top-down symmetric deconstruction approach provides a novel alternative means to successfully identify a useful polypeptide "building block" for subsequent "bottom-up" de novo design of target protein architecture.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 3T3 Cells
  • Amino Acid Sequence
  • Animals
  • Crystallography, X-Ray
  • Fibroblast Growth Factor 1 / chemistry
  • Fibroblast Growth Factor 1 / genetics
  • Humans
  • Mice
  • Molecular Sequence Data
  • Peptides / chemistry*
  • Peptides / genetics
  • Protein Denaturation
  • Protein Folding*
  • Protein Structure, Secondary*
  • Protein Structure, Tertiary*
  • Receptor, Fibroblast Growth Factor, Type 1 / chemistry
  • Receptor, Fibroblast Growth Factor, Type 1 / genetics
  • Sequence Alignment
  • Sequence Homology, Amino Acid


  • Peptides
  • Fibroblast Growth Factor 1
  • FGFR1 protein, human
  • Receptor, Fibroblast Growth Factor, Type 1

Associated data

  • PDB/3O3Q