Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode
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Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode. / Shenol, Aslihan; Tenente, Ricardo; Lückmann, Michael; Frimurer, Thomas M.; Schwartz, Thue W.
I: Nature Communications, Bind 15, 5364, 2024.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode
AU - Shenol, Aslihan
AU - Tenente, Ricardo
AU - Lückmann, Michael
AU - Frimurer, Thomas M.
AU - Schwartz, Thue W.
N1 - Publisher Copyright: © The Author(s) 2024.
PY - 2024
Y1 - 2024
N2 - A surprisingly clear picture of the allosteric mechanism connecting G protein-coupled receptor agonists with G protein binding—and back – is revealed by a puzzle of thirty novel 3D structures of the hydroxycarboxylic acid receptor 2 (HCAR2) in complex with eight different orthosteric and a single allosteric agonist. HCAR2 is a sensor of β-hydroxybutyrate, niacin and certain anti-inflammatory drugs. Surprisingly, agonists with and without on-target side effects bound very similarly and in a completely occluded orthosteric binding site. Thus, despite the many structures we are still left with a pertinent need to understand the molecular dynamics of this and similar systems.
AB - A surprisingly clear picture of the allosteric mechanism connecting G protein-coupled receptor agonists with G protein binding—and back – is revealed by a puzzle of thirty novel 3D structures of the hydroxycarboxylic acid receptor 2 (HCAR2) in complex with eight different orthosteric and a single allosteric agonist. HCAR2 is a sensor of β-hydroxybutyrate, niacin and certain anti-inflammatory drugs. Surprisingly, agonists with and without on-target side effects bound very similarly and in a completely occluded orthosteric binding site. Thus, despite the many structures we are still left with a pertinent need to understand the molecular dynamics of this and similar systems.
U2 - 10.1038/s41467-024-49536-y
DO - 10.1038/s41467-024-49536-y
M3 - Journal article
C2 - 38918366
AN - SCOPUS:85196845948
VL - 15
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 5364
ER -
ID: 396637618