Figure 1.

Inhibition of PTP1B. (A) Alignments of the backbone of PTP1B in competitively inhibited (yellow and orange, Protein Data Bank entry 2F71) and allosterically inhibited (gray and black, Protein Data Bank entry 1T4J) poses. The binding of substrates and competitive inhibitors to the active site causes the WPD loop to adopt a closed (orange) conformation that stabilizes the C-terminal α7 helix through an allosteric network; this helix is unresolvable in allosterically inhibited, noncompetitively inhibited, and uninhibited structures, which exhibit WPD-open conformations (black). (B) Chemical structure of abietic acid (AA). (C) Initial rates of PTP1B-catalyzed hydrolysis of pNPP in the presence of increasing concentrations of AA. Lines show a fit to a model for mixed inhibition (Table S2A). (D) In this model, the inhibitor (I) binds to the enzyme (E) and the enzyme–substrate complex (ES) with different affinities. Error bars in panel C denote the standard error (n ≥ 3 independent reactions).