A model of the lutropin/choriogonadotropin receptor: Insights into the structural and functional effects of constitutively activating mutations

A model of the seven transmembrane helical domain (7-TM) of the human lutropin receptor was constructed from the 2D electron density map of bovine rhodopsin and a set of geometric parameters derived from a published analysis of 204 G-protein coupled receptor sequences. The Self-Consistent Ensemble Optimization method was applied to predict overall side chain packing. The model is consistent with the general helical packing properties expected of transmembrane proteins and suggests possible structural and functional effects of constitutively activating mutations. A tightly packed hydrophobic cluster formed between the intracellular halves of TM5 and TM6, as well as a specific H-bonding network formed between the central regions of TM6 and TM7, is proposed to be critical for stabilizing the inactive form of the receptor. The model suggests that single activating mutations perturb the specific interactions of TM6 with TM5 and TM7, either by disrupting the hydrophobic packing between TM5 and TM6, or by weakening the H-bonds between TM6 and TM7.