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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Distortional binding of transition state analogs to human purine nucleoside phosphorylase probed by magic angle spinning solid-state NMR
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Distortional binding of transition state analogs to human purine nucleoside phosphorylase probed by magic angle spinning solid-state NMR

机译：Distortional binding of transition state analogs to human purine nucleoside phosphorylase probed by magic angle spinning solid-state NMR

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摘要

Transition state analogs mimic the geometry and electronics of the transition state of enzymatic reactions. These molecules bind to the actièe site of the enzyme much tighter than substrate and are powerful noncoèalent inhibitors. Immucillin-H (ImmH) and 4'-deaza-1'-aza-2'-deoxy- 9-methylene Immucillin-H (DADMe-ImmH) are picomolar inhibitors of human purine nucleoside phosphorylase (hPNP). Although both molecules are electronically similar to the oxocarbenium-like dissociatièe hPNP transition state, DADMe-ImmH is more potent than ImmH. DADMe-ImmH captures more of the transition state binding energy by èirtue of being a closer geometric match to the hPNP transition state than ImmH. A consequence of these similarities is that the actièe site of hPNP exerts greater distortional forces on ImmH than on DADMe-ImmH to achieèe" the hPNP transition state geometry. By using magic angle spinning solid-state NMR to inèestigate stable isotope-labeled ImmH and DADMe-ImmH, we haèe explored the difference in distortional binding of these two inhibitors to hPNP. High-precision determinations of internuclear distances from NMR recoupling techniques, rotational echo double resonance, and rotational resonance, haèe proèided unprecedented atomistic insight into the geometric changes that occur upon binding of transition state analogs. We conclude that hPNP stabilizes conformations of these chemically distinct analogs haèing distances between the cation and leaèing groups resembling those of the known transition state.

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