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Crystal structure of Stefin A in complex with cathepsin H: N-terminal residues of inhibitors can adapt to the active sites of endo- and exopeptidases.
- Source :
-
Journal of molecular biology [J Mol Biol] 2003 Feb 21; Vol. 326 (3), pp. 875-85. - Publication Year :
- 2003
-
Abstract
- Binding of cystatin-type inhibitors to papain-like exopeptidases cannot be explained by the stefin B-papain complex. The crystal structure of human stefin A bound to an aminopeptidase, porcine cathepsin H, has been determined in monoclinic and orthorhombic crystal forms at 2.8A and 2.4A resolutions, respectively. The asymmetric unit of each form contains four complexes. The structures are similar to the stefin B-papain complex, but with a few distinct differences. On binding, the N-terminal residues of stefin A adopt the form of a hook, which pushes away cathepsin H mini-chain residues and distorts the structure of the short four residue insertion (Lys155A-Asp155D) unique to cathepsin H. Comparison with the structure of isolated cathepsin H shows that the rims of the cathepsin H structure are slightly displaced (up to 1A) from their position in the free enzyme. Furthermore, comparison with the stefin B-papain complex showed that molecules of stefin A bind about 0.8A deeper into the active site cleft of cathepsin H than stefin B into papain. The approach of stefin A to cathepsin H induces structural changes along the interaction surface of both molecules, whereas no such changes were observed in the stefin B-papain complex. Carboxymethylation of papain seems to have prevented the formation of the genuine binding geometry between a papain-like enzyme and a cystatin-type inhibitor as we observe it in the structure presented here.
- Subjects :
- Animals
Binding Sites
Cathepsin H
Cathepsins metabolism
Crystallography, X-Ray
Cystatin A
Cystatins metabolism
Cysteine Endopeptidases metabolism
Humans
Models, Molecular
Protein Conformation
Recombinant Proteins chemistry
Recombinant Proteins metabolism
Swine
Cathepsins chemistry
Cystatins chemistry
Cysteine Endopeptidases chemistry
Endopeptidases metabolism
Exopeptidases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2836
- Volume :
- 326
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of molecular biology
- Publication Type :
- Academic Journal
- Accession number :
- 12581647
- Full Text :
- https://doi.org/10.1016/s0022-2836(02)01432-8