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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Polizzi, NF; Wu, Y; Lemmin, T; Maxwell, AM; Zhang, S-Q; Rawson, J; Beratan, DN; Therien, MJ; DeGrado, WF

Published Date

  • December 2017

Published In

Volume / Issue

  • 9 / 12

Start / End Page

  • 1157 - 1164

PubMed ID

  • 29168496

Pubmed Central ID

  • 29168496

Electronic International Standard Serial Number (EISSN)

  • 1755-4349

International Standard Serial Number (ISSN)

  • 1755-4330

Digital Object Identifier (DOI)

  • 10.1038/nchem.2846

Language

  • eng