Journal
SCIENCE ADVANCES
Volume 7, Issue 27, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abh3805
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Funding
- Novo Nordisk Foundation Synergy program [NNF15OC0016670]
- Challenge Program (REPIN) [NNF18OC0033926]
- Lundbeck Foundation
- Lundbeck Foundation Initiative BRAINSTRUC [R155-2015-2666]
- Novo Nordisk Foundation [NNF18OC0032608]
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This study uses methods such as small-angle X-ray scattering to investigate the structure of the human growth hormone receptor, revealing a broad structural ensemble in hGHR that emphasizes the need to view signaling in disease states from an ensemble perspective. This is the first experimental model of any full-length cytokine receptor in a lipid membrane.
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.
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