Title : Detailed molecular comparison between the inhibition mode of A/B-type carboxypeptidases in the zymogen state and by the endogenous inhibitor
latexin
Abstract :
- Treatment of advanced stages of prostate carcinoma with histone-deacetylase inhibitors entails expression of human procarboxypeptidase-A4 (hPCPA4)
- The three-dimensional structure of hPCPA4 has been solved and shows the features of related metallocarboxypeptidase zymogens, with a preformed alpha/beta/-hydrolase active-enzyme moiety ( hCPA4 ) and an inhibiting pro-domain (PD)
- The protease moiety recalls a sphere, out of which a spherical cone has been cut
- This results in a funnel-like structure, at the bottom of which the active-site cleft resides
- The border of this funnel is shaped by loops, which are responsible for the interaction with the PD, characterised by a large interface area and relatively few contacts
- Such an inhibitory mode is evocative of the recently reported structure of the human inhibitor latexin in its complex with hCPA4
- The main contacting structure of latexin is similar to the one employed for PD inhibition
- In both cases, active-site blocking relies mainly on a loop provided by the central part of a beta sheet
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*Output_Site_Fusion* (sent_index,
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