Crystal structure of carboxypeptidase A complexed with D-cysteine at 1.75 angstrom - Inhibitor-induced conformational changes

D-Cysteine differs from the antiarthritis drug D-penicillamine by only two methyl groups on the beta-carbon yet inhibits carboxypeptidase A (CPD) by a distinct mechanism: D-cysteine binds tightly to the active site zinc, whil e D-penicillamine catalyzes metal removal. To investigate the structural ba sis for this difference, we solved the crystal structure of carboxypeptidas e A complexed with D-cysteine (D-Cys) at 1.75-Angstrom resolution. D-Cys bi nds the active site zinc with a sulfur ligand and forms additional interact ions with surrounding side chains of the enzyme. The structure explains the difference in potency between D-Cys and L-Cys and provides insight into th e mechanism of D-penicillamine inhibition. D-Cys binding ind;ces a concerte d motion of the side chains around the zinc ion, similar to that found in o ther carboxypeptidase-inhibitor crystal structures and along a limited path . Analysis of concerted motions of CPD and CPD-inhibitor crystal structures reveals a clustering of these structures into distinct groups. Using the r estricted conformational flexibility of a drug target in this type of analy sis could greatly enhance efficiency in drug design.