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

van Aalten, D. M. F., Chong, C. R., Joshua-Tor, L. (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

URL: https://www.ncbi.nlm.nih.gov/pubmed/10955996
DOI: 10.1021/bi000952h

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 Deposited: 20 Mar 2012 19:39
Last Modified: 05 Sep 2017 19:31
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Dataset ID:
URI: http://repository.cshl.edu/id/eprint/25495

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