8UTD

CryoEM Structure of HCA2-Gi1 in complex with MK-1903

8UTD の概要

• エントリーDOI: 10.2210/pdb8utd/pdb
• EMDBエントリー: 42538
• 分子名称: Hydroxycarboxylic acid receptor 2, scFv16, Guanine nucleotide-binding protein G(i) subunit alpha-1, ... (6 entities in total)
• 機能のキーワード: gpcr, hca2, mk 1903, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 158855.24

構造登録者

Krumm, B.E.,Kang, H.J.,Diberto, J.F.,Kapolka, N.J.,Gumpper, R.H.,Olsen, R.H.J.,Huang, X.P.,Zhang, S.,Fay, J.F.,Roth, B.L. (登録日: 2023-10-30, 公開日: 2025-02-26, 最終更新日: 2025-05-14)

主引用文献

Kang, H.J.,Krumm, B.E.,Tassou, A.,Geron, M.,DiBerto, J.F.,Kapolka, N.J.,Gumpper, R.H.,Sakamoto, K.,Dewran Kocak, D.,Olsen, R.H.J.,Huang, X.P.,Zhang, S.,Huang, K.L.,Zaidi, S.A.,Nguyen, M.T.,Jo, M.J.,Katritch, V.,Fay, J.F.,Scherrer, G.,Roth, B.L.
Structure-guided design of a peripherally restricted chemogenetic system.
Cell, 187:7433-7449.e20, 2024

PubMed Abstract: Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools for remotely controlling cellular signaling, neural activity, behavior, and physiology. Using a structure-guided approach, we provide a peripherally restricted Gi-DREADD, hydroxycarboxylic acid receptor DREADD (HCAD), whose native receptor is minimally expressed in the brain, and a chemical actuator that does not cross the blood-brain barrier (BBB). This was accomplished by combined mutagenesis, analoging via an ultra-large make-on-demand library, structural determination of the designed DREADD receptor via cryoelectron microscopy (cryo-EM), and validation of HCAD function. Expression and activation of HCAD in dorsal root ganglion (DRG) neurons inhibit action potential (AP) firing and reduce both acute and tissue-injury-induced inflammatory pain. The HCAD chemogenetic system expands the possibilities for studying numerous peripheral systems with little adverse effects on the central nervous system (CNS). The structure-guided approach used to generate HCAD also has the potential to accelerate the development of emerging chemogenetic tools for basic and translational sciences.

PubMed: 39631393
DOI: 10.1016/j.cell.2024.11.001

実験手法

ELECTRON MICROSCOPY (3.24 Å)