De novo design of a non-local β-sheet protein with high stability and accuracy

Details

• Alternative Title:
  Nat Struct Mol Biol
• Personal Author:
  Marcos, Enrique ; Chidyausiku, Tamuka M. ; McShan, Andrew C. ; Evangelidis, Thomas ; Nerli, Santrupti ; Carter, Lauren ; Nivón, Lucas G. ; Davis, Audrey ; Oberdorfer, Gustav ; Tripsianes, Konstantinos ; Sgourakis, Nikolaos G. ; Baker, David
• Description:
  β-sheet proteins carry out critical functions in biology, and hence are attractive scaffolds for computational protein design. Despite this potential, de novo design of all-β-sheet proteins from first principles lags far behind the design of all-α or mixed-αβ domains owing to their non-local nature and the tendency of exposed β-strand edges to aggregate. Through study of loops connecting unpaired β-strands (β-arches), we have identified a series of structural relationships between loop geometry, side chain directionality and β-strand length that arise from hydrogen bonding and packing constraints on regular β-sheet structures. We use these rules to de novo design jellyroll structures with double-stranded β-helices formed by eight antiparallel β-strands. The nuclear magnetic resonance structure of a hyperthermostable design closely matched the computational model, demonstrating accurate control over the β-sheet structure and loop geometry. Our results open the door to the design of a broad range of non-local β-sheet protein structures.
• Subjects:
  Article
• Source:
  Nat Struct Mol Biol. 25(11):1028-1034
• Pubmed ID:
  30374087
• Pubmed Central ID:
  PMC6219906
• Document Type:
  Journal Article
• Funding:
  Howard Hughes Medical Institute/United States ; R35 GM125034/NIGMS NIH HHS/National Institute of General Medical Sciences/United States ; S10 OD018455/ODCDC CDC HHS/Office of the Director/United States
• Volume:
  25
• Issue:
  11
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:10ebf5270bd06a9c65e21b120c5047d94342707193141c8186eda88eddc6edf4
• Download URL:
  https://stacks.cdc.gov/view/cdc/80356/cdc_80356_DS1.pdf
• File Type:
  [PDF - 889.31 KB ]