Structural Modeling of Human Growth Hormone Receptor using Computational Simulations and NMR Spectroscopy

Abstract

Growth hormone receptor (GHR) is a central component of growth hormone (GH) induced signaling pathway. It is engaged in various cell functions related to growth and metabolism. Despite its crucial role in these functions, knowledge of its structure remains elusive, especially the transmembrane (TM) domain that bridges extracellular signals to the cytosolic downstream recipients. We modeled the TM domain structures of the active and inactive receptors using temperature replica-exchange simulations and further tested their structural stability and intrinsic dynamics in POPC bilayers with a total of 15.6 μs molecular dynamics simulations. Cross-validation experiments were also carried out. These include (i) performing window-exchange umbrella sampling simulations with the inter-helical distances as the reaction coordinates to find the energetically most favorable human GHR TM dimer structures and (ii) extracting structural information from H1-N15 HSQC NMR spectra. The results of the three independent experiments well compliment each other. The active and inactive states of human GHR adopt different structural features. The difference is subtle, mostly in the interfacial residues, and is presumably caused by rotation and piston motions of the TM helices.