Open AccessOrder and disorder—An integrative structure of the full-length human growth hormone receptor
Author(s) -
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 LindorffLarsen,
Lise Arleth,
Birthe B. Kragelund
Publication year - 2021
Publication title -
science advances
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.928
H-Index - 146
ISSN - 2375-2548
DOI - 10.1126/sciadv.abh3805
Subject(s) - small angle x ray scattering , growth hormone receptor , order and disorder , computational biology , molecular dynamics , structural biology , crystallography , scattering , biophysics , biology , chemistry , physics , optics , microbiology and biotechnology , growth hormone , hormone , biochemistry , computational chemistry , quantum mechanics
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.