Polyproline-rod approach to isolating protein targets of bioactive small molecules: Isolation of a new target of indomethacin

Shin Ichi Sato, Youngjoo Kwon, Shinji Kamisuki, Neeta Srivastava, Qian Mao, Yoshinori Kawazoe, Motonari Uesugi

Research output: Contribution to journalArticlepeer-review

105 Scopus citations

Abstract

Identification of protein targets of bioactive small molecules has been a technical hurdle of chemical genetics. Here we report a polyproline-rod approach to isolating protein targets of small molecules from cell lysates. The results indicate that insertion of a long, rigid polyproline helix between a small-molecule bait and a biotin tag boosts the capacity of affinity purification and thereby permits isolation of low-abundance or low-affinity proteins. In the course of the proof-of-concept experiments, we isolated glyoxalase 1 (GLO1) as a new target of indomethacin, a widely used antiinflammatory drug. Molecular biological experiments suggest that inhibition of GLO1 enzyme activity is related to the clinically recognized beneficial side effects of the indomethacin family of nonsteroidal antiinflammatory drugs.

Original languageEnglish
Pages (from-to)873-880
Number of pages8
JournalJournal of the American Chemical Society
Volume129
Issue number4
DOIs
StatePublished - 31 Jan 2007

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