De novo design of a hyperstable non-natural protein-ligand complex with sub-Å accuracy

Nat Chem. 2017 Dec;9(12):1157-1164. doi: 10.1038/nchem.2846. Epub 2017 Aug 21.


Protein catalysis requires the atomic-level orchestration of side chains, substrates and cofactors, and yet the ability to design a small-molecule-binding protein entirely from first principles with a precisely predetermined structure has not been demonstrated. Here we report the design of a novel protein, PS1, that binds a highly electron-deficient non-natural porphyrin at temperatures up to 100 °C. The high-resolution structure of holo-PS1 is in sub-Å agreement with the design. The structure of apo-PS1 retains the remote core packing of the holoprotein, with a flexible binding region that is predisposed to ligand binding with the desired geometry. Our results illustrate the unification of core packing and binding-site definition as a central principle of ligand-binding protein design.

Publication types

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

MeSH terms

  • Ligands
  • Models, Molecular
  • Porphyrins / chemistry*
  • Proteins / chemistry*
  • Temperature


  • Ligands
  • Porphyrins
  • Proteins