Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
11
|
| pubmed:dateCreated |
1994-7-7
|
| pubmed:abstractText |
Constrained analogues of phenylalanine have been conceptually designed for analyzing the binding pockets of Phe7 (S7) and Phe8 (S8), two aromatic residues important for the pharmacological properties of SP, i.e., L-tetrahydroisoquinoleic acid, L-diphenylalanine, L-9-fluorenylglycine (Flg), 2-indanylglycine, the diastereomers of L-1-indanylglycine (Ing) and L-1-benz[f]indanylglycine (Bfi), and the Z and E isomers of dehydrophenylalanine (delta ZPhe, delta EPhe). Binding studies were performed with appropriate ligands and tissue preparations allowing the discrimination of the three tachykinin binding sites, NK-1, NK-2, and NK-3. The potencies of these agonists were evaluated in the guinea pig ileum bioassay. According to the binding data, we can conclude that the S7 subsite is small, only the gauche (-) probe [(2S,3S)-Ing7]SP presents a high affinity for specific NK-1 binding sites. Surprisingly, the [delta EPhe7]SP analogue, which projects the aromatic ring toward the trans orientation, is over 40-fold more potent than the Z isomer, [delta ZPhe7]SP. A plausible explanation of these conflictual results is that either the binding protein quenches the minor trans rotamer of [(2S,3S)-Ing7]SP in solution or this constrained amino acid side chain rotates when inserted in the protein. In position 8, the high binding affinities of [Flg8]SP and [(2S,3S)-Bfi8]SP suggest that the S8 subsite is large enough to accept two aromatic rings in the gauche (-) and one aromatic ring in the trans direction. Peptides bearing two conformational probes in positions 7, 8, or 9 led to postulate that S7, S8, and S9 subsites are independent from each other. The volumes available for side chains 7 and 8 can be estimated to be close to 110 and 240 A3, respectively. The large volume of the S8 subsite raises question on the localization of the SP-binding site in the NK-1 receptor. If SP were to bind in the transmembrane domains, the cleft defined by the seven transmembrane segments must rearrange during the binding process in order to bind a peptide in an alpha-helical structure and at least one large binding subsite in position 8. Thus, indirect topographical analysis with constrained amino acids might contribute to the analysis of the receptor/ligand dynamics. Finally, this study demonstrates that a good knowledge of the peptidic backbone structure and a combination of constrained amino acids are prerequisites to confidently attribute the preferred orientation(s) of an amino acid side chain.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Fluorenes,
http://linkedlifedata.com/resource/pubmed/chemical/Glycine,
http://linkedlifedata.com/resource/pubmed/chemical/Indans,
http://linkedlifedata.com/resource/pubmed/chemical/Phenylalanine,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Neurokinin-1,
http://linkedlifedata.com/resource/pubmed/chemical/Substance P
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
May
|
| pubmed:issn |
0022-2623
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
27
|
| pubmed:volume |
37
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
1586-601
|
| pubmed:dateRevised |
2006-11-15
|
| pubmed:meshHeading |
pubmed-meshheading:7515443-Amino Acid Sequence,
pubmed-meshheading:7515443-Animals,
pubmed-meshheading:7515443-Binding Sites,
pubmed-meshheading:7515443-Brain,
pubmed-meshheading:7515443-Cell Membrane,
pubmed-meshheading:7515443-Fluorenes,
pubmed-meshheading:7515443-Glycine,
pubmed-meshheading:7515443-Guinea Pigs,
pubmed-meshheading:7515443-Ileum,
pubmed-meshheading:7515443-Indans,
pubmed-meshheading:7515443-Male,
pubmed-meshheading:7515443-Molecular Sequence Data,
pubmed-meshheading:7515443-Molecular Structure,
pubmed-meshheading:7515443-Phenylalanine,
pubmed-meshheading:7515443-Protein Conformation,
pubmed-meshheading:7515443-Rats,
pubmed-meshheading:7515443-Receptors, Neurokinin-1,
pubmed-meshheading:7515443-Stereoisomerism,
pubmed-meshheading:7515443-Structure-Activity Relationship,
pubmed-meshheading:7515443-Substance P,
pubmed-meshheading:7515443-Synaptosomes,
pubmed-meshheading:7515443-Thermodynamics
|
| pubmed:year |
1994
|
| pubmed:articleTitle |
Design and synthesis of side-chain conformationally restricted phenylalanines and their use for structure-activity studies on tachykinin NK-1 receptor.
|
| pubmed:affiliation |
Laboratoire de Chimie Organique Biologique, CNRS URA 493, Université P. et M. Curie, Paris, France.
|
| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
|