Direct Chemical Activation of a Rationally Engineered Signaling Enzyme.

摘要: Few chemical strategies for activating enzymes have been developed. Here we show that a biarsenical compound (FlAsH) can directly activate rationally engineered protein tyrosine phosphatase (Shp2 PTP) by disrupting autoinhibitory interactions between Shp2's N-terminal SH2 domain and its PTP domain. We found introducing tricysteine motif at loop of N-SH2 confers affinity FlAsH; binding FlAsH to the cysteine-enriched relieves inhibitory interdomain interaction substantially increases enzyme's activity. Activation Shp2 is substrate independent observed in contexts both purified enzyme complex proteomes. A means could be useful investigating roles signaling oncogenesis, loop-targeting strategy described herein provide blueprint development target-specific activators other autoinhibited enzymes.