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 α/β/-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 β sheet.
Key words. Metallocarboxypeptidase, X-ray crystal structure, carboxypeptidase inhibitor, latexin
Footnotes
R. Garcia-Castellanos and R. Bonet-Figueredo contributed equally to this study and share first authorship.
Received 28 April 2005; received after revision 1 June 2005; accepted 29 June 2005
Contributor Information
J. Vendrell, FAX: +34 935 811 264, Email: josep.vendrell@uab.es
F. X. Gomis-Rütha, FAX: +34 932 045 904, Email: xgrcri@ibmb.csic.es