van Aalten, D. M. F., Chong, C. R., Joshua-Tor, L. (August 2000) Crystal structure of carboxypeptidase A complexed with D-cysteine at 1.75 A - inhibitor-induced conformational changes. Biochemistry, 39 (33). pp. 10082-10089. ISSN 0006-2960 (Public Dataset)
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-Angstrom 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 ind;ces 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.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | SITE-DIRECTED MUTAGENESIS site directed mutagenesis ESSENTIAL DYNAMICS essential dynamics MATRIX matrix METALLOPROTEINASES metalloproteinases MOLECULAR-DYNAMICS molecular dynamics PROTEIN STRUCTURES protein structures SUBSTRATE-ANALOGS substrate analogs BINDING PROTEIN binding protein ZINC ENZYMES Zinc enzymes RESOLUTION resolution THERMOLYSIN thermolysin |
| Subjects: | Investigative techniques and equipment > X-Ray Diffraction bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein structure rendering Investigative techniques and equipment > x ray crystallography |
| CSHL Authors: | |
| Communities: | CSHL labs > Joshua-Tor lab |
| Depositing User: | CSHL Librarian |
| Date: | August 2000 |
| Date Deposited: | 20 Mar 2012 19:39 |
| Last Modified: | 05 Sep 2017 19:31 |
| Related URLs: | |
| Dataset ID: | |
| URI: | https://repository.cshl.edu/id/eprint/25495 |
Actions (login required)
 |
Administrator's edit/view item |