Order and disorder—An integrative structure of the full-length human growth hormone receptor
Noah Kassem, Raúl Araya-Secchi, Katrine Bugge, Abigail Barclay, Helena Steinocher, Adree Khondker, Yong Wang, Aneta J. Lenard, Jochen Bürck, Cagla Sahin, Anne S. Ulrich, Michael Landreh, Martin Cramer Pedersen, Maikel C. Rheinstädter, Per Amstrup Pedersen, Kresten Lindorff‐Larsen, Lise Arleth, Birthe B. Kragelund
Abstract
Because of its small size (70 kilodalton) and large content of structural disorder (>50%), the human growth hormone receptor (hGHR) falls between the cracks of conventional high-resolution structural biology methods. Here, we study the structure of the full-length hGHR in nanodiscs with small-angle x-ray scattering (SAXS) as the foundation. We develop an approach that combines SAXS, x-ray diffraction, and NMR spectroscopy data obtained on individual domains and integrate these through molecular dynamics simulations to interpret SAXS data on the full-length hGHR in nanodiscs. The hGHR domains reorient freely, resulting in a broad structural ensemble, emphasizing the need to take an ensemble view on signaling of relevance to disease states. The structure provides the first experimental model of any full-length cytokine receptor in a lipid membrane and exemplifies how integrating experimental data from several techniques computationally may access structures of membrane proteins with long, disordered regions, a widespread phenomenon in biology.