9EQG

CryoEM structure of human full-length alpha1beta3gamma2L GABA(A)R in complex with GABA and puerarin

This is a non-PDB format compatible entry.

Summary for 9EQG

• Entry DOI: 10.2210/pdb9eqg/pdb
• EMDB information: 19907
• Descriptor: Gamma-aminobutyric acid receptor subunit alpha-1, [(2R)-1-octadecanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phospho ryl]oxy-propan-2-yl] (8Z)-icosa-5,8,11,14-tetraenoate, HEXADECANE, ... (18 entities in total)
• Functional Keywords: gaba(a) receptor, inhibitory synapse, gaba, puerarin, fat regulation, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 286635.83

Authors

Kasaragod, V.B.,Aricescu, A.R. (deposition date: 2024-03-21, release date: 2024-09-18, Last modification date: 2024-11-06)

Primary citation

Lyu, Q.,Xue, W.,Liu, R.,Ma, Q.,Kasaragod, V.B.,Sun, S.,Li, Q.,Chen, Y.,Yuan, M.,Yang, Y.,Zhang, B.,Nie, A.,Jia, S.,Shen, C.,Gao, P.,Rong, W.,Yu, C.,Bi, Y.,Zhang, C.,Nan, F.,Ning, G.,Rao, Z.,Yang, X.,Wang, J.,Wang, W.
A brain-to-gut signal controls intestinal fat absorption.
Nature, 634:936-943, 2024

PubMed Abstract: Although fat is a crucial source of energy in diets, excessive intake leads to obesity. Fat absorption in the gut is prevailingly thought to occur organ-autonomously by diffusion. Whether the process is controlled by the brain-to-gut axis, however, remains largely unknown. Here we demonstrate that the dorsal motor nucleus of vagus (DMV) plays a key part in this process. Inactivation of DMV neurons reduces intestinal fat absorption and consequently causes weight loss, whereas activation of the DMV increases fat absorption and weight gain. Notably, the inactivation of a subpopulation of DMV neurons that project to the jejunum shortens the length of microvilli, thereby reducing fat absorption. Moreover, we identify a natural compound, puerarin, that mimics the suppression of the DMV-vagus pathway, which in turn leads to reduced fat absorption. Photoaffinity chemical methods and cryogenic electron microscopy of the structure of a GABA receptor-puerarin complex reveal that puerarin binds to an allosteric modulatory site. Notably, conditional Gabra1 knockout in the DMV largely abolishes puerarin-induced intestinal fat loss. In summary, we discover that suppression of the DMV-vagus-jejunum axis controls intestinal fat absorption by shortening the length of microvilli and illustrate the therapeutic potential of puerarin binding to GABRA1 in fat loss.

PubMed: 39261733
DOI: 10.1038/s41586-024-07929-5

Experimental method

ELECTRON MICROSCOPY (2.4 Å)