Turning the growth hormone receptor on: Evidence that hormone binding induces subunit rotation |
| |
Authors: | David Poger Alan E Mark |
| |
Institution: | 1. School of Chemistry and Molecular Biosciences, Faculty of Science, The University of Queensland, Brisbane, QLD 4072, Australia;2. Institute for Molecular Bioscience, Division of Chemistry and Structural Biology, The University of Queensland, Brisbane, QLD 4072, Australia |
| |
Abstract: | Atomistic molecular dynamics simulations have been used to investigate the conformational changes associated with the binding of human growth hormone (hGH) to the extracellular domains (ECD) of the human growth hormone receptor (hGHR), thereby shedding light on the mechanism of activation. It is shown that the removal of hGH from the hormone‐bound receptor complex results in a counter‐clockwise rotation of the twosubunits relative to each other by 30°–64° (average 45° ± 14°), in close agreement in terms of both the magnitude and direction of the rotation with that proposed based on mutagenesis experiments. In addition to providing evidence to support a rotational activation mechanism, the simulations have enabled the nature of the interaction interfaces in both the cytokine‐bound and unliganded hGHR states to be analyzed in detail. Proteins 2010. © 2009 Wiley‐Liss, Inc. |
| |
Keywords: | cytokine receptor growth hormone molecular dynamics simulation receptor activation signal transduction |
|
|