Crystal Structure of Carboxypeptidase A Complexed with D-Cysteine at 1.75 Å - Inhibitor-Induced Conformational Changes
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- 作者：Daan M. F. van Aalten ; Curtis R. Chong ; and Leemor Joshua-Tor
- 刊名：Biochemistry
- 出版年：2000
- 出版时间：August 22, 2000
- 年：2000
- 卷：39
- 期：33
- 页码：10082 - 10089
- 全文大小：422K
- 年卷期：v.39,no.33(August 22, 2000)
- ISSN：1520-4995
文摘
D-Cysteine differs from the antiarthritis drug D-penicillamine by only two methyl groups onthe 
-carbon yet inhibits carboxypeptidase A (CPD) by a distinct mechanism: D-cysteine binds tightly tothe active site zinc, while D-penicillamine catalyzes metal removal. To investigate the structural basis forthis difference, we solved the crystal structure of carboxypeptidase A complexed with D-cysteine (D-Cys)at 1.75-Å resolution. D-Cys binds the active site zinc with a sulfur ligand and forms additional interactionswith surrounding side chains of the enzyme. The structure explains the difference in potency betweenD-Cys and L-Cys and provides insight into the mechanism of D-penicillamine inhibition. D-Cys bindinginduces a concerted motion of the side chains around the zinc ion, similar to that found in othercarboxypeptidase-inhibitor crystal structures and along a limited path. Analysis of concerted motions ofCPD 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 enhanceefficiency in drug design.
-carbon yet inhibits carboxypeptidase A (CPD) by a distinct mechanism: D-cysteine binds tightly tothe active site zinc, while D-penicillamine catalyzes metal removal. To investigate the structural basis forthis difference, we solved the crystal structure of carboxypeptidase A complexed with D-cysteine (D-Cys)at 1.75-Å resolution. D-Cys binds the active site zinc with a sulfur ligand and forms additional interactionswith surrounding side chains of the enzyme. The structure explains the difference in potency betweenD-Cys and L-Cys and provides insight into the mechanism of D-penicillamine inhibition. D-Cys bindinginduces a concerted motion of the side chains around the zinc ion, similar to that found in othercarboxypeptidase-inhibitor crystal structures and along a limited path. Analysis of concerted motions ofCPD 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 enhanceefficiency in drug design.