Structural Mechanisms of Slow-Onset, Two-Step Enzyme Inhibition
Whereas the ability to recognize and measure the kinetics of slow-onset enzyme inhibition is fully developed, our understanding of the structural mechanisms is still evolving. This literature review focuses on the two-step process in which a rapid-equilibrium enzyme/ inhibitor (EI) complex isomerizes slowly and reversibly to a tighter EI* complex. Although structural details are still mostly lacking, some generalities have been realized. The most central finding is that protein conformational changes are often subtle and sometimes even difficult to identify. Most interactions occur in the initial complex formation and the isomerization represents critical but minor adjustments. When available, energetic estimates based on these structural refinements match the differences in free energy of interaction calculated from equilibrium constants for EI and EI* and thus are sufficient to explain the kinetics. Less often described and defined for two-step slow inhibition, larger polypeptide movement induced by inhibitor binding such as loop or flap rearrangements has been observed or hypothesized. Separately, ionization of inhibitor has been critical in several systems and implies poor solvent accessibility of bound inhibitor. Finally, as described for the two cyclooxygenase isozymes, movement of inhibitor into and through the protein matrix can give rise to slow-onset kinetics.
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Document Type: Research Article
Publication date: January 1, 2010
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