Computational model of wild-type and I131T mutant TRH receptors in complex with TRH and Gq

The “active-like” state of human TRHR (UniProt entry {"type":"entrez-protein","attrs":{"text":"P34981","term_id":"464921","term_text":"P34981"}}P34981) in complex with TRH and Gq was built using a combination of structural templates. Crystal structures of active μ-opioid receptor [Protein Data Bank Identification (PDB ID): 5C1M] (20), the complex between β₂-adrenergic receptor and Gs protein (PDB ID: 3SN6) (11) and Gq protein (PDB ID: 3AH8) (21), were used (Supplemental Methods). TRH was docked into the “active-like” conformation of TRHR using MOE (Chemical Computing Group Inc., Montreal, QC, Canada) (Supplemental Methods). To evaluate the effect of the I131^ICL2T mutation in the TRHR-Gq interface, we performed molecular dynamics (MD) simulations of wild-type and mutant receptors (Supplemental Methods).