Linked Life Data

8961350

Source:http://linkedlifedata.com/resource/pubmed/id/8961350

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
11
pubmed:dateCreated
1997-3-17
pubmed:abstractText
Two binding modes of the isobutyl-NH-Eps-Leu-Pro inhibitor to cathepsin B have been proposed. Molecular docking using an empirical force field was carried out to distinguish between the two modes. The search began with manual docking, followed by random perturbations of the docking conformation and cycles of Monte Carlo minimization. Finally, molecular dynamics was carried out for the most favorable docking conformations. The present calculations predict that the isobutyl-NH-Eps-Leu-Pro inhibitor preferentially binds to the S' rather than the S subsites of cathepsin B. The S' binding mode prediction is supported by the X-ray crystal structure of cathepsin B bound to a closely related ethyl-O-Eps-Ile-Pro inhibitor, which was found to bind in the S'subsite with the C-terminal epoxy ring carbon making a covalent bond to the sulfur atom of Cys29. This agreement, in turn, validates our docking strategy. Furthermore, the calculations provide evidence that the dominant contribution to the total stabilization energy of the enzyme-inhibitor complex stems from the strong electrostatic interaction between the negatively charged C-terminal carboxylate group of the ligand and the positively charged imidazolium rings of His110 and His111. The latter are stabilized and held in an optimal orientation for interactions with the C-terminal end of the ligand through a salt bridge between the side chains of His110 and Asp22. By comparison with the crystal structure, some insight into the specificity of the epoxyldipeptide family towards cathepsin B inhibition has been extracted. Both the characteristics of the enzyme (e.g. subsite size and hydrophobicity) as well as the nature of the inhibitor influence the selectivity of an inhibitor towards an enzyme.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0269-2139
pubmed:author
pubmed:issnType
Print
pubmed:volume
9
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
977-86
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
1996
pubmed:articleTitle
The binding mode of an E-64 analog to the active site of cathepsin B.
pubmed:affiliation
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't