8JV6

Cryo-EM structure of the zebrafish P2X4 receptor in complex with BAY-1797

Summary for 8JV6

• Entry DOI: 10.2210/pdb8jv6/pdb
• EMDB information: 36669
• Descriptor: P2X purinoceptor, 2-acetamido-2-deoxy-beta-D-glucopyranose, N-[4-(3-chloranylphenoxy)-3-sulfamoyl-phenyl]-2-phenyl-ethanamide (3 entities in total)
• Functional Keywords: atp, allosteric modulator, channel, transport protein
• Biological source: Danio rerio (zebrafish)
• Total number of polymer chains: 3
• Total formula weight: 121996.63

Authors

Hattori, M.,Shen, C. (deposition date: 2023-06-27, release date: 2023-10-18, Last modification date: 2024-11-06)

Primary citation

Shen, C.,Zhang, Y.,Cui, W.,Zhao, Y.,Sheng, D.,Teng, X.,Shao, M.,Ichikawa, M.,Wang, J.,Hattori, M.
Structural insights into the allosteric inhibition of P2X4 receptors.
Nat Commun, 14:6437-6437, 2023

PubMed Abstract: P2X receptors are ATP-activated cation channels, and the P2X4 subtype plays important roles in the immune system and the central nervous system, particularly in neuropathic pain. Therefore, P2X4 receptors are of increasing interest as potential drug targets. Here, we report the cryo-EM structures of the zebrafish P2X4 receptor in complex with two P2X4 subtype-specific antagonists, BX430 and BAY-1797. Both antagonists bind to the same allosteric site located at the subunit interface at the top of the extracellular domain. Structure-based mutational analysis by electrophysiology identified the important residues for the allosteric inhibition of both zebrafish and human P2X4 receptors. Structural comparison revealed the ligand-dependent structural rearrangement of the binding pocket to stabilize the binding of allosteric modulators, which in turn would prevent the structural changes of the extracellular domain associated with channel activation. Furthermore, comparison with the previously reported P2X structures of other subtypes provided mechanistic insights into subtype-specific allosteric inhibition.

PubMed: 37833294
DOI: 10.1038/s41467-023-42164-y

Experimental method

ELECTRON MICROSCOPY (3.43 Å)