Article: Dimerization of G-protein-coupled receptors.
Journal of medicinal chemistry
2001 Volume 44, Issue 26, Page(s) 4595–4614
Abstract: ... of amino acid conservation, has been applied to over 700 aligned G-protein-coupled receptor (GPCR) sequences ... oligomerization. The application of the evolutionary trace method to 113 aligned G-protein sequences resulted ... beta/gamma and regulator of G-protein signaling (RGS) binding. The other G-protein functional site ...
Abstract | The evolutionary trace (ET) method, a data mining approach for determining significant levels of amino acid conservation, has been applied to over 700 aligned G-protein-coupled receptor (GPCR) sequences. The method predicted the occurrence of functionally important clusters of residues on the external faces of helices 5 and 6 for each family or subfamily of receptors; similar clusters were observed on helices 2 and 3. The probability that these clusters are not random was determined using Monte Carlo techniques. The cluster on helices 5 and 6 is consistent with both 5,6-contact and 5,6-domain swapped dimer formation; the possible equivalence of these two types of dimer is discussed because this relates to activation by homo- and heterodimers. The observation of a functionally important cluster of residues on helices 2 and 3 is novel, and some possible interpretations are given, including heterodimerization and oligomerization. The application of the evolutionary trace method to 113 aligned G-protein sequences resulted in the identification of two functional sites. One large, well-defined site is clearly identified with adenyl cyclase, beta/gamma and regulator of G-protein signaling (RGS) binding. The other G-protein functional site, which extends from the ras-like domain onto the helical domain, has the correct size and electrostatic properties for GPCR dimer binding. The implications of these results are discussed in terms of the conformational changes required in the G-protein for activation by a receptor dimer. Further, the implications of GPCR dimerization for medicinal chemistry are discussed in the context of these ET results. |
---|---|
MeSH term(s) | Amino Acid Sequence ; Consensus Sequence ; Dimerization ; GTP-Binding Proteins/chemistry ; Models, Molecular ; Monte Carlo Method ; Mutation ; Receptors, Cell Surface/chemistry ; Receptors, Cell Surface/genetics |
Chemical Substances | Receptors, Cell Surface ; GTP-Binding Proteins (EC 3.6.1.-) |
Language | English |
Publishing date | 2001-12-20 |
Publishing country | United States |
Document type | Journal Article ; Research Support, Non-U.S. Gov't |
ZDB-ID | 218133-2 |
ISSN | 1520-4804 ; 0022-2623 |
ISSN (online) | 1520-4804 |
ISSN | 0022-2623 |
DOI | 10.1021/jm010290+ |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
More links
Kategorien
In stock of ZB MED Cologne/Königswinter
Zs.B 151: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG) |
|||
Zs.MB 1: Show issues |
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.