Abstract
The optimal inhibitory responsiveness of calf brain membranal (Na+ + K+)-dependent ATPase to cardioactive sterols was determined to be consistent with a model depicting a three-point or area interaction between inhibitor and a complementary binding site on the enzyme. Each functional ATPase molecule could be inhibited reversibly by 1 molecule of sterol at the binding site. The A component of the binding site interacted optimally with the sugar portion of an aglycone monosaccharide rather than that of an aglycone di-, tri-, or tetrasaccharide or the 3β-hydroxyl group of the aglycone. The B component of the binding site yielded optimal enzyme inhibition as a result of interaction with the sterol 14-hydroxyl group. Relative affinities at the C component of the binding site were related to the following order of preference for the lactone ring substituted at position 17β of the sterol: α-pyrone > crotonolactone > γ-butyro1actone. Although the sterol lactone rings possess large dipole moments, the compounds most inhibitory toward (Na+ + K+)-ATPase favored ring planarity and a relatively extensive π-electron system. Binding of the crotonolactone and α-pyrone substituents to the C component was postulated to result from multiple interactions, one or more of which are independent of the lactone ring group dipole moment, namely, π-π system interaction or π-complex formation.
ACKNOWLEDGMENTS We thank Drs. S. W. Dale and E. O. Oswald for assistance in collection and interpretation of the NMR and infrared spectra.
- Copyright ©, 1970, by Academic Press Inc.
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