(1) Department of Biochemistry, George Wise faculty of Life Sciences,
Tel-Aviv University, Tel-Aviv 69978,ISRAEL
(2) School of Chemistry, Tel-Aviv University, Tel-Aviv 69978,ISRAEL
The GnRH receptor is a member of the G-protein coupled receptors (GPCRs) which initiate cellular signaling pathways upon binding to ligands. An important feature to this group of receptors is that they comprise of seven transmembrane (TM) helices connected by relatively short loops with varying lengths of N-terminal and C-terminal "tails".
Knowledge of the three dimensional structure of GPCRs is crucial for understanding the structure-function realtionships. The poor solubility of GPCRs in polar solvents and their large size make it is extremely difficult to determine X-ray or NMR structures of GPCRs. Thus, a computational theoretical study of the 3D structure of GPCR is an important tool in understanding of the structure-function relationships of these receptors.
Many attempts have been made to predict the TM domains of GPCRs using bacteriorhodopsin (BR) as a template. However , the extremely low sequence homology of BR with other GPCR and the fact that BR possesses a hydrophobic co-factor, retinal, in the core of the molecule indicate that important features of GPCR ,such as the packing shape of the helix bundle may differ from BR.
The aim of our study is to construct a new reliable atomistic model of the GnRH receptor by a new approach based on physico-chemical and geometrical constrains. We address the receptor modeling task as a hierarchical process, starting with a coarse model and gradually refining it by introducing more detailed physico-chemical properties. The modeling starts with assessing the best packing conformation of the seven helices in the membrane. This step involves reducing the TM helices to two dimensional dials and then, based on amphiphilicity and geometrical properties, exploring the optimal packing shape. Using the best 2D model as a template an initial 3D model is constructed and then refined by adding helical tilts and introducing specific residue-residue interactions (van der Waals and electrostatic). Finally a full atomistic model for the molecule is constructed. should be stressed,that once the modeling procedure is optimized (in the case of the GnRH receptor) the same approach will be easily applied to all other GPCR molecules. Understanding the structure-function realtionships of the GnRHR receptor will open a new vista for the development of a peptide and non-peptide agonists and antagonists for treatments of fertility and cancer.