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There is growing interest in peptide or small protein based drugs targeting G protein-coupled receptors (GPCRs) for improved subtype selectivity over small molecules. Naturally occurring toxins represent rich sources of such ligands. AdTx1 (ρ-Da1a), a three-finger toxin (3FTx) from the green Mamba Snake, selectively binds and antagonizes α-adrenoceptors. Here, we present the cryo-electron microscopy structure of α1A-adrenoceptor in complex with AdTx1. The structure reveals the molecular mechanism of the subtype selectivity and antagonist activity of AdTx1 for α1A-adrenoceptor, which is different from those revealed by the only 3FTx-GPCR structure reported so far, the Muscarinic toxins 7 (MT7) - Muscarinic acetylcholine receptor 1 (M1AChR) structure. Based on the structural information, we further engineered the AdTx1 and enhanced its antagonist activity by introducing three mutations. The results highlight the potential of developing potent toxin drugs towards GPCRs based on the 3FTx scaffold and structural information.
The structure of the α1A-adrenoceptor in complex with AdTx1 elucidates its subtype selectivity and antagonistic mechanism, and provides guidance for further engineering to enhance its activity.
Details
Venom;
Adrenergic receptors;
Independent sample;
Data processing;
Electron microscopy;
G protein-coupled receptors;
Drug development;
Molecular modelling;
Acetylcholine receptors (muscarinic);
Ligands;
Data collection;
Snakes;
Drug delivery;
Peptides;
Toxins;
Post traumatic stress disorder;
Competition;
Proteins
; Toyoda, Yosuke 4
; Kong, Fang 3
; Sun, Xiaoou 4 ; Xu, Xinyu 2
; Yan, Chuangye 3
; Liu, Xiangyu 5
1 Tsinghua University, State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Pharmaceutical Sciences, Beijing, China (GRID:grid.12527.33) (ISNI:0000 0001 0662 3178); Tsinghua University, School of Medicine, Beijing, China (GRID:grid.12527.33) (ISNI:0000 0001 0662 3178); Tsinghua University, Beijing Frontier Research Center for Biological Structure, Beijing Advanced Innovation Center for Structural Biology, Beijing, China (GRID:grid.12527.33) (ISNI:0000 0001 0662 3178)
2 Tsinghua University, State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Pharmaceutical Sciences, Beijing, China (GRID:grid.12527.33) (ISNI:0000 0001 0662 3178); Tsinghua University, Beijing Frontier Research Center for Biological Structure, Beijing Advanced Innovation Center for Structural Biology, Beijing, China (GRID:grid.12527.33) (ISNI:0000 0001 0662 3178)
3 Tsinghua University, Beijing Frontier Research Center for Biological Structure, Beijing Advanced Innovation Center for Structural Biology, Beijing, China (GRID:grid.12527.33) (ISNI:0000 0001 0662 3178); Tsinghua University, State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Beijing, China (GRID:grid.12527.33) (ISNI:0000 0001 0662 3178)
4 Tsinghua University, School of Medicine, Beijing, China (GRID:grid.12527.33) (ISNI:0000 0001 0662 3178); Tsinghua University, Beijing Frontier Research Center for Biological Structure, Beijing Advanced Innovation Center for Structural Biology, Beijing, China (GRID:grid.12527.33) (ISNI:0000 0001 0662 3178)
5 Tsinghua University, State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Pharmaceutical Sciences, Beijing, China (GRID:grid.12527.33) (ISNI:0000 0001 0662 3178); Tsinghua University, Beijing Frontier Research Center for Biological Structure, Beijing Advanced Innovation Center for Structural Biology, Beijing, China (GRID:grid.12527.33) (ISNI:0000 0001 0662 3178); Peking University, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China (GRID:grid.11135.37) (ISNI:0000 0001 2256 9319)