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Article
Open AccessXanomeline displays concomitant orthosteric and allosteric binding modes at the M4 mAChR
The M4 muscarinic acetylcholine receptor (M4 mAChR) has emerged as a drug target of high therapeutic interest due to its expression in regions of the brain involved in the regulation of psychosis, cognition, and ...
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Article
Open AccessStructural basis of efficacy-driven ligand selectivity at GPCRs
A drug’s selectivity for target receptors is essential to its therapeutic utility, but achieving selectivity between similar receptors is challenging. The serendipitous discovery of ligands that stimulate targ...
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Article
Open AccessAuthor Correction: Structural basis of efficacy-driven ligand selectivity at GPCRs
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Article
Open AccessThe P2X1 receptor as a therapeutic target
Within the family of purinergic receptors, the P2X1 receptor is a ligand-gated ion channel that plays a role in urogenital, immune and cardiovascular function. Specifically, the P2X1 receptor has been implicat...
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Article
Selective G protein signaling driven by substance P–neurokinin receptor dynamics
The neuropeptide substance P (SP) is important in pain and inflammation. SP activates the neurokinin-1 receptor (NK1R) to signal via Gq and Gs proteins. Neurokinin A also activates NK1R, but leads to selective Gq
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Article
Positive allosteric mechanisms of adenosine A1 receptor-mediated analgesia
The adenosine A1 receptor (A1R) is a promising therapeutic target for non-opioid analgesic agents to treat neuropathic pain1,2. However, development of analgesic orthosteric A1R agonists has failed because of a l...
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Article
Structural insights into G-protein-coupled receptor allostery
G-protein-coupled receptors (GPCRs) are key cell-surface proteins that transduce external environmental cues into biochemical signals across the membrane. GPCRs are intrinsically allosteric proteins; they inte...
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Article
Structure of the adenosine-bound human adenosine A1 receptor–Gi complex
The class A adenosine A1 receptor (A1R) is a G-protein-coupled receptor that preferentially couples to inhibitory Gi/o heterotrimeric G proteins, has been implicated in numerous diseases, yet remains poorly targe...
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Article
Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor–Gs complex
The structure of the glucagon-like peptide 1 receptor (GLP-1R) with its biased agonist exendin-P5 sheds light on both receptor activation and the mechanism of biased agonism.
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Article
Open AccessThe action of a negative allosteric modulator at the dopamine D2 receptor is dependent upon sodium ions
Sodium ions (Na+) allosterically modulate the binding of orthosteric agonists and antagonists to many class A G protein-coupled receptors, including the dopamine D2 receptor (D2R). Experimental and computational ...
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Article
Phase-plate cryo-EM structure of a class B GPCR–G-protein complex
Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, such as osteoporosis, diabetes and obesity. Here we report the structure of a full-length class B receptor, the calc...
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Article
Crystal structures of the M1 and M4 muscarinic acetylcholine receptors
Muscarinic M1–M5 acetylcholine receptors are G-protein-coupled receptors that regulate many vital functions of the central and peripheral nervous systems. In particular, the M1 and M4 receptor subtypes have em...
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Article
An autoinhibitory helix in the C-terminal region of phospholipase C-β mediates Gαq activation
By examining the structure of phospholipase C-β, an autoinhibitory helix that interacts with the catalytic core of this enzyme is now identified. Disrupting this interaction enhances basal activity and decreas...
