1F57

Crystal structure of carboxypeptidase A complexed with D-cysteine at 1.75 A - inhibitor-induced conformational changes.

(2000) Biochemistry 39: 10082-10089

• PubMed: 10955996 Search on PubMed
• DOI: https://doi.org/10.1021/bi000952h
• Primary Citation of Related Structures:  
  1F57


• PubMed Abstract: 
  

  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, while D-penicillamine catalyzes metal removal. To investigate the structural basis for this difference, we solved the crystal structure of carboxypeptidase A complexed with D-cysteine (D-Cys) at 1.75-A resolution. D-Cys binds the active site zinc with a sulfur ligand and forms additional interactions with surrounding side chains of the enzyme. The structure explains the difference in potency between D-Cys and L-Cys and provides insight into the mechanism of D-penicillamine inhibition. D-Cys binding induces a concerted motion of the side chains around the zinc ion, similar to that found in other 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 restricted conformational flexibility of a drug target in this type of analysis could greatly enhance efficiency in drug design.

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Organizational Affiliation: 

W. M. Keck Structural Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.