English
 
Help Privacy Policy Disclaimer
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
  Impact of aromatic residues within transmembrane helix 6 of the human gonadotropin-releasing hormone receptor upon agonist and antagonist binding

Hövelmann, S., Hoffmann, S. H., Kühne, R., ter Laak, T., Reiländer, H., & Beckers, T. (2002). Impact of aromatic residues within transmembrane helix 6 of the human gonadotropin-releasing hormone receptor upon agonist and antagonist binding. Biochemistry, 41(4), 1129-1136. doi:10.1021/bi0113162.

Item is

Files

show Files

Locators

show

Creators

show
hide
 Creators:
Hövelmann, Sascha1, Author
Hoffmann, Silke H.1, Author
Kühne, Ronald2, Author
ter Laak, Ton3, Author
Reiländer, Helmut4, Author              
Beckers, Thomas1, Author
Affiliations:
1Department of Cancer Research, ASTA Medica AG, 60314 Frankfurt/Main, Germany, ou_persistent22              
2Institute of Molecular Pharmacology, Alfred-Kowalke-Strasse 4, D-10315 Berlin, Germany, ou_persistent22              
3Farmacochemie, DiVision of Chemistry,Vrije UniVersiteit Amsterdam, De Boelelaan 1083, NL-1081 HV Amsterdam, ou_persistent22              
4Department of Molecular Membrane Biology, Max Planck Institute of Biophysics, Max Planck Society, ou_2068290              

Content

show
hide
Free keywords: Protein-coupled receptors; Human gnrh receptor; Ligand interaction; Expression; Sites; Overexpression; Hypogonadism; Activation; Contribute; Mechanisms; Binding; X-ray structure
 Abstract: To investigate the impact of aromatic residues within transmembrane helix 6 (TMH6) of the human gonadotropin-releasing hormone receptor (GnRH-R) on agonist and antagonist binding, residues pY283, Y284, W289, Y290, W291, and F202 were exchanged to alanine and analyzed comprehensively in functional reporter gene and ligand binding assays. Whereas receptor mutants Y283A, Y281A, and W291A were capable of neither ligand binding nor signal transduction, mutants W219A, Y290A, and F292A were functional: the F292A mutant behaved like wild-type receptor, while mutants W289A and Y290A differentiated between agonistic and antagonistic ligands. On the basis of the high-resolution X-ray structure of bovine rhodopsin as well as available data on GnRH-R mutants, models for ligand-receptor interactions are proposed. The model for D-Trp6-GnRH (Triptorelin) binding, representing a superagonistic ligand, is in full accordance to available data. Furthermore, new interactions are proposed: pGlu1 interacts with N212 in transmembrane helix 5, Tyr5 with Y290, and D-Trp6 with W289. The binding behavior of mutants W289A and Y290A corresponds to the proposed binding model for the antagonist Cetrorelix. In summary, our data as presented indicate that Y290 plays a key function in agonist but not antagonist binding.

Details

show
hide
Language(s): eng - English
 Dates: 2001-09-262001-06-222002-06-032002-01-01
 Publication Status: Published in print
 Pages: 8
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1021/bi0113162
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: Biochemistry
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: Columbus, Ohio : American Chemical Society
Pages: - Volume / Issue: 41 (4) Sequence Number: - Start / End Page: 1129 - 1136 Identifier: ISSN: 0006-2960
CoNE: https://pure.mpg.de/cone/journals/resource/954925384103