G- Protein coupled receptors

The GPCR projects are mainly focused on ligand design for GPCR's using molecular dynamics and simulated annealing methods in combination with pharmacophore mapping and virtual screening techniques. Two post-doctoral researchers investigate the interaction of ligands with GPCR’s in collaboration with two pharmaceutical companies. Homology modeling tools in particular were developed to produce models of protein structures based on a known 3D-structure of a template protein. Specifically in the case of GPCR modeling, molecular dynamics simulations of GPCR’s based on the high resolution X-ray structure of bovine rhodopsin yielded receptor models which accorded well with experimental data and showed predictive powers for ligand design. Evaluated binding site models deduced from homology modeling or from ex-perimentally derived complex structures could be used in virtual screening. The aim of these methods is to check the binding probability for thousands of different chemi-cals available in commercial or non-commercial databases using fast computer algorithms.

The interaction of agonists and antagonists with the gonadotropin releasing hormone receptor (GnRHR) is the subject of cooperation with academic groups (Univ. Ulm, Univ. Utrecht) and the Zentaris AG (Frankfurt/M). Based on the high resolution X-ray structure of bovine rhodopsin as well as available data on GnRH-R mutants, models for ligand-receptor interactions are developed. The model for D-Trp6-GnRH (Triptore-lin) binding, representing a super agonistic ligand, is in full accordance to available data. Furthermore new interactions were proposed. The binding behaviour of mutants W289A and Y290A corresponds to the proposed binding model for the antagonist Cetrorelix indicating that Y290 plays a key function in agonist, but not antago-nist binding. Based on 3D-pharmacophores derived on the models, new GnRH- antagonists were synthesized and successfully tested.

In cooperation with the Dept. of Endocrinology (Univ. Ulm) the Ala171Thr mutation of the GnRHR was recognized as a cause of familial gonadotropin deficiency. Molecular modeling and dynamic simulation of the Ala171Thr GnRH receptor suggested the introduction of a stable hydrogen bond between residue Thr171 and Tyr119 side chains at 2 Å distance. Though spatially distant from the GnRH ligand binding site, this hydrogen bond impedes conformational mobility of the TMH3 and TMH4 domains required for sequential ligand binding and receptor activation, thus stabilizing the GnRH receptor in its inactive conformation.

In cooperation with the Dept. Endocrinology (Univ. Utrecht) we studied the the ligand selectivity of different GnRH- analogs to the catfish GnRH receptor. This receptor differs from its mammalian counterparts in showing a very low affinity for the hypothalamic GnRH forms, i.s. for catfish GnRH (cfGnRH) and for mammalian GnRH (mGnRH), and a very high affinity for the highly conserved mesencephalic GnRH, namely chicken GnRH-II (cGnRH-II). According to our binding models, studies on the binding characteristics of the catfish GnRH receptor for cfGnRH, mGnRH and cGnRH-II as well as for synthetic chimeric GnRHs varying at positions 5, 7 and 8 re-vealed that the low affinity of the catfish receptor for cfGnRH can be improved by re-placing Leu7 by Trp and/or Asn8 by either Tyr or Arg. After testing cfGnRH, mGnRH and cGnRH-II as well as the chimeric GnRHs on Asp304Ala-, Asp304Glu- and Asp304Asn-mutant catfish GnRH receptors, the Asp304 residue of the catfish receptor was demonstrated to mediate the recognition of Arg8 in mGnRH as well as in the chimeric peptides [Arg8]cfGnRH and [Arg8]cGnRH-II, but seems to be less important for the recognition of Tyr8 in cGnRH-II.

Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
Robert-Roessle-Str. 10
13125 Berlin, Germany
+4930 94793 - 100 
+4930 94793 - 109 (Fax)

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