Control of repeat-protein curvature by computational protein design

Nat Struct Mol Biol. 2015 Feb;22(2):167-74. doi: 10.1038/nsmb.2938. Epub 2015 Jan 12.

Abstract

Shape complementarity is an important component of molecular recognition, and the ability to precisely adjust the shape of a binding scaffold to match a target of interest would greatly facilitate the creation of high-affinity protein reagents and therapeutics. Here we describe a general approach to control the shape of the binding surface on repeat-protein scaffolds and apply it to leucine-rich-repeat proteins. First, self-compatible building-block modules are designed that, when polymerized, generate surfaces with unique but constant curvatures. Second, a set of junction modules that connect the different building blocks are designed. Finally, new proteins with custom-designed shapes are generated by appropriately combining building-block and junction modules. Crystal structures of the designs illustrate the power of the approach in controlling repeat-protein curvature.

Publication types

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

MeSH terms

  • Crystallography, X-Ray
  • Leucine-Rich Repeat Proteins
  • Protein Conformation
  • Protein Engineering / methods
  • Proteins / chemistry*

Substances

  • Leucine-Rich Repeat Proteins
  • Proteins

Associated data

  • PDB/4R58
  • PDB/4R5C
  • PDB/4R5D
  • PDB/4R6F
  • PDB/4R6G
  • PDB/4R6J