G-protein coupled receptors (GPCRs) transduce signals from extracellular messengers (e.g. hormones, neurotransmitters) to cytoplasmic G-proteins tha act as effectors in a variety of intracellular signaling pathways. The luteinizing hormone receptor (LHR) mediates gonadal steroid hormone production in males and females. Specific mutations of the LHR gene in males cause a condition called testotoxicosis. These mutations are known to significantly increase the basal signaling level of LHR (constitutive activity), presumably by mimicking the ligand- bound conformational state of the receptor. It is known that the seven helical transmembrane (7-TM) domain of LHR and all GPCRs structurally rearrange upon ligand binding. The two-dimensional structure of rhodopsin (RH), a member of the GPCR family, has been solved at low resolution. To date, no three-dimensional GPCR structure has been solved. We are using modeling to hypothesize the three-dimensional structure of the LHR receptor. This work is based on the 2D electron density map of RH and other data, and considers the non-signaling form of LHR. We have built and compared static models of both wild-type and naturally occurring constitutively active mutant forms of LHR, and have found some ke differences in side chain packing that appear to correlate with energetic destabilization of the non-signaling form of the 7-TM domain.
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