8SL3

Human adenylyl Cyclase 5 in complex with Gbg

8SL3 の概要

• エントリーDOI: 10.2210/pdb8sl3/pdb
• EMDBエントリー: 40572
• 分子名称: Adenylate cyclase type 5, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (4 entities in total)
• 機能のキーワード: adenylyl cyclase, g-proteins, complex, signaling protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 184618.87

構造登録者

Yen, Y.C.,Tesmer, J.J.G. (登録日: 2023-04-20, 公開日: 2024-04-03, 最終更新日: 2024-09-04)

主引用文献

Yen, Y.C.,Li, Y.,Chen, C.L.,Klose, T.,Watts, V.J.,Dessauer, C.W.,Tesmer, J.J.G.
Structure of adenylyl cyclase 5 in complex with G beta gamma offers insights into ADCY5-related dyskinesia.
Nat.Struct.Mol.Biol., 31:1189-1197, 2024

PubMed Abstract: The nine different membrane-anchored adenylyl cyclase isoforms (AC1-9) in mammals are stimulated by the heterotrimeric G protein, Gα, but their response to Gβγ regulation is isoform specific. In the present study, we report cryo-electron microscope structures of ligand-free AC5 in complex with Gβγ and a dimeric form of AC5 that could be involved in its regulation. Gβγ binds to a coiled-coil domain that links the AC transmembrane region to its catalytic core as well as to a region (C) that is known to be a hub for isoform-specific regulation. We confirmed the Gβγ interaction with both purified proteins and cell-based assays. Gain-of-function mutations in AC5 associated with human familial dyskinesia are located at the interface of AC5 with Gβγ and show reduced conditional activation by Gβγ, emphasizing the importance of the observed interaction for motor function in humans. We propose a molecular mechanism wherein Gβγ either prevents dimerization of AC5 or allosterically modulates the coiled-coil domain, and hence the catalytic core. As our mechanistic understanding of how individual AC isoforms are uniquely regulated is limited, studies such as this may provide new avenues for isoform-specific drug development.

PubMed: 38589608
DOI: 10.1038/s41594-024-01263-0

実験手法

ELECTRON MICROSCOPY (7 Å)