Order and disorder - An integrative structure of the full-length human growth hormone receptor

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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.

TidsskriftScience Advances
Udgave nummer27
Antal sider20
StatusUdgivet - 2021

Bibliografisk note

Funding Information:
This work has been supported by the Novo Nordisk Foundation Synergy program (#NNF15OC0016670; to B.B.K. and L.A.) and Challenge Program (REPIN, #NNF18OC0033926; to B.B.K.), the Lundbeck Foundation (to B.B.K.), and the Lundbeck Foundation Initiative BRAINSTRUC (R155-2015-2666; to K.L.-L., B.B.K., and L.A.). We authors acknowledge the ILL, France for the allocated SEC-SANS beamtime as well as the European Synchrotron Radiation Facility (ESRF) and PETRAIII at the Deutsches Elektronen-Synchrotron (DESY), Germany for the allocated SAXS beamtime. We acknowledge access to computational resources from the Danish National Supercomputer for Life Sciences (Computerome) and the ROBUST Resource for Biomolecular Simulations (supported by the Novo Nordisk Foundation, NNF18OC0032608).

Publisher Copyright:
Copyright © 2021 The Authors, some rights reserved.

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