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The structure of the complex of thermolysin and the inhibitor
(2-benzyl-3-mercaptopropanoyl)-L-alanylglycinamide has been determined by X-ray
crystallography at a resolution of 1.9 A and refined to a crystallographic
residual of 18.4%. The binding of this potent, specific inhibitor to thermolysin
(Ki = 7.5 X 10(-7) M) serves as a model for the inhibition of zinc peptidases by
substrate-analogue mercaptans. The study shows that the mercaptan inhibitor
binds to thermolysin with the sulfur, presumably in the anionic form,
tetrahedrally coordinated to the zinc and displacing a water molecule bound to
the native enzyme. This is the first direct determination of the mode of binding
of a mercaptan inhibitor to a zinc peptidase and confirms the geometry of
binding expected on general grounds [Ondetti, M. A., Condon, M. E., Reid, J.,
Sabo, E. F., Cheung, H. S., & Cushman, D. W. (1979) Biochemistry 18,
1427-1430; Nishino, N., & Powers, J. C. (1979) Biochemistry 18, 4340-4347]
and inferred from previous spectroscopic studies [Holmquist, B., & Vallee,
B. L. (1979) Proc. Natl. Acad. Sci. U.S.A. 76, 6216-6220].
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