Here is the X-ray structure of human carboxypeptidase A2 complexed with a peptide inhibitor from the medicinal leach, reported by Reverter et al (2000) Nature Structural Biology 7(4), 322-8. [Protein Data Bank code 1DTD.]
This is an interactive display using the CHIME software. Rotate the molecule by dragging it with the left mouse button. Change its appearance by clicking the image with the right mouse button to show the structure more clearly. Click HERE for a brief reminder of the main CHIME commands, or HERE for a full chime tutorial. Using the right mouse button, set "Display" to cartoons. Click again and set "Color" to chain. This will help you to distinguish between the two polypeptides. Click again and set "Select" via "atom" to zinc (ZN). Click again and set "Display" via "spacefill" to Van der Waals radii. Rotate the ensemble with the left button, and experiment with different views to see how the active site is constructed around the zinc atom, and how the carboxyl terminus of proteins are degraded one residue at a time. The particular peptide is an indigestible morsel. The carboxypeptidase structure was not known in such detail when captopril was designed in the 1970's and in any case ACE removes two amino acids while carboxypeptidase removes only one. |
Nevertheless a basic understanding of the carboxypeptidase structure helped Cushman and Ondetti to conceptualise the active centre of ACE, and design inhibitors that would block it.