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

Kassem, N.; Araya-Secchi, R.; Bugge, K.; Barclay, A.; Steinocher, H.; Khondker, A.; Wang, Y.; Lenard, A. J.; Bürck, J. 1; Sahin, C.; Ulrich, A. S. 1; Landreh, M.; Pedersen, M. C.; Rheinstädter, M. C.; Pedersen, P. A.; Lindorff-Larsen, K.; Arleth, L.; Kragelund, B. B.
1 Institut für Biologische Grenzflächen (IBG), Karlsruher Institut für Technologie (KIT)


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.

Verlagsausgabe §
DOI: 10.5445/IR/1000135841
Veröffentlicht am 27.07.2021
DOI: 10.1126/sciadv.abh3805
Zitationen: 19
Zitationen: 28
Cover der Publikation
Zugehörige Institution(en) am KIT Institut für Biologische Grenzflächen (IBG)
Publikationstyp Zeitschriftenaufsatz
Publikationsjahr 2021
Sprache Englisch
Identifikator ISSN: 2375-2548
KITopen-ID: 1000135841
HGF-Programm 47.14.01 (POF IV, LK 01) Molekular Information Processing in Cellular Systems
Erschienen in Science Advances
Verlag American Association for the Advancement of Science (AAAS)
Band 7
Heft 27
Seiten Art.-Nr.: eabh3805
Vorab online veröffentlicht am 30.06.2021
Nachgewiesen in Web of Science
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