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Summary: letters
nature structural biology · volume 5 number 11 · november 1998 945
While the majority of proteins fold rapidly and spontaneous-
ly to their native states, the extracellular bacterial protease
-lytic protease (LP) has a t1/2 for folding of ~2,000 years,
corresponding to a folding barrier of 30 kcal mol1. LP is
synthesized as a pro-enzyme where its pro region (Pro) acts
as a foldase to stabilize the transition state for the folding
reaction. Pro also functions as a potent folding catalyst when
supplied as a separate polypeptide chain, accelerating the
rate of LP folding by a factor of 3 × 109. In the absence of
Pro, LP folds only partially to a stable molten globule-like
intermediate state. Addition of Pro to this intermediate leads
to rapid formation of native LP. Here we report the crystal
structures of Pro and of the non-covalent inhibitory complex
between Pro and native LP. The C-shaped Pro surrounds
the C-terminal -barrel domain of the folded protease, form-
ing a large complementary interface. Regions of extensive
hydration in the interface explain how Pro binds tightly to
the native state, yet even more tightly to the folding transi-
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