Linked Life Data

8286362

Source:http://linkedlifedata.com/resource/pubmed/id/8286362

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
1994-2-24
pubmed:abstractText
Determination of the X-ray structure of thermolysin-inhibitor complexes has proven useful in aiding our understanding of the mode of binding of inhibitors of related, physiologically important, mammalian zinc peptidases including neutral endopeptidase EC 3.4.24.11 and angiotensin-converting enzyme. Here we describe the mode of binding to crystalline thermolysin of N-[1-(2(R,S)-carboxy-4-phenylbutyl)-cyclopentylcarbonyl]-(S) -tryptophan (CCT). CCT is an analogue of both candoxatrilat, a potent inhibitor of neutral endopeptidase 24.11, and of the 5-indanyl ester prodrug candoxatril, which is under clinical evaluation as a potential therapy for congestive heart failure. CCT differs from the previously studied N-carboxyalkyl dipeptide CLT [N-(S)-(1-carboxy-3-phenylpropyl)-(S)-leucyl-(S)-tryptophan] in several important respects. It has a highly constrained gem-cyclopentyl P1' substituent and lacks the characteristic imino nitrogen substituent of CLT. The structure determination shows that, notwithstanding the conformational influence of the gem-cyclopentyl substituent, CCT binds within the active site of thermolysin in a similar manner to CLT. Although the characteristic hydrogen bond between the imino nitrogen of CLT and thermolysin is absent in CCT, the affinities of the two inhibitors for the enzyme are virtually identical. These results illustrate the importance of considering not only those hydrogen bonds that are formed in an enzyme-ligand complex but also the other hydrogen bonds that may be lost due to desolvation of the enzyme and ligand on formation of the complex. In addition, the overall conformational demands placed upon a ligand in order to achieve receptor interaction may be critically important.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0006-2960
pubmed:author
pubmed:issnType
Print
pubmed:day
11
pubmed:volume
33
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
51-6
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
1994
pubmed:articleTitle
Inhibition of thermolysin and neutral endopeptidase 24.11 by a novel glutaramide derivative: X-ray structure determination of the thermolysin-inhibitor complex.
pubmed:affiliation
Howard Hughes Medical Institute, University of Oregon, Eugene 97403.
pubmed:publicationType
Journal Article, Comparative Study, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't