Trapping a transition state in a computationally designed protein bottle

Aaron D. Pearson, Jeremy H. Mills, Yifan Song, Fariborz Nasertorabi, Gye Won Han, David Baker, Raymond C. Stevens, Peter G. Schultz

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

The fleeting lifetimes of the transition states (TSs) of chemical reactions make determination of their three-dimensional structures by diffraction methods a challenge. Here, we used packing interactions within the core of a protein to stabilize the planar TS conformation for rotation around the central carbon-carbon bond of biphenyl so that it could be directly observed by x-ray crystallography. The computational protein design software Rosetta was used to design a pocket within threonyl-transfer RNA synthetase from the thermophile Pyrococcus abyssi that forms complementary van der Waals interactions with a planar biphenyl.This latter moiety was introduced biosynthetically as the side chain of the noncanonical amino acid p-biphenylalanine. Through iterative rounds of computational design and structural analysis, we identified a protein in which the side chain of p-biphenylalanine is trapped in the energetically disfavored, coplanar conformation of the TS of the bond rotation reaction.

Original languageEnglish (US)
Pages (from-to)863-867
Number of pages5
JournalScience
Volume347
Issue number6224
DOIs
StatePublished - Feb 20 2015
Externally publishedYes

ASJC Scopus subject areas

  • General

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