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Article
Open AccessImpact of secretin receptor homo-dimerization on natural ligand binding
Class B G protein-coupled receptors can form dimeric complexes important for high potency biological effects. Here, we apply pharmacological, biochemical, and biophysical techniques to cells and membranes expr...
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Article
Structural insight into selectivity of amylin and calcitonin receptor agonists
Amylin receptors (AMYRs), heterodimers of the calcitonin receptor (CTR) and one of three receptor activity-modifying proteins, are promising obesity targets. A hallmark of AMYR activation by Amy is the formati...
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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 AccessGWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification
Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on ‘around the clock’ glucoregula...
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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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Open AccessAuthor Correction: Structural basis of efficacy-driven ligand selectivity at GPCRs
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Article
Open AccessUnderstanding VPAC receptor family peptide binding and selectivity
The vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) receptors are key regulators of neurological processes. Despite recent structural data, a comprehensive un...
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Article
Structural and functional diversity among agonist-bound states of the GLP-1 receptor
Recent advances in G-protein-coupled receptor (GPCR) structural elucidation have strengthened previous hypotheses that multidimensional signal propagation mediated by these receptors depends, in part, on their...
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Article
Open AccessDynamics of GLP-1R peptide agonist engagement are correlated with kinetics of G protein activation
The glucagon-like peptide-1 receptor (GLP-1R) has broad physiological roles and is a validated target for treatment of metabolic disorders. Despite recent advances in GLP-1R structure elucidation, detailed mec...
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Article
Open AccessCognitive behavioral markers of neurodevelopmental trajectories in rodents
Between adolescence and adulthood, the brain critically undergoes maturation and refinement of synaptic and neural circuits that shape cognitive processing. Adolescence also represents a vulnerable period for ...
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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
Open AccessRoutine sub-2.5 Å cryo-EM structure determination of GPCRs
Cryo-electron microscopy (cryo-EM) of small membrane proteins, such as G protein-coupled receptors (GPCRs), remains challenging. Pushing the performance boundaries of the technique requires quantitative knowle...
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Article
Open AccessStructure and dynamics of the active Gs-coupled human secretin receptor
The class B secretin GPCR (SecR) has broad physiological effects, with target potential for treatment of metabolic and cardiovascular disease. Molecular understanding of SecR binding and activation is importan...
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Article
Biased M1-muscarinic-receptor-mutant mice inform the design of next-generation drugs
Cholinesterase inhibitors, the current frontline symptomatic treatment for Alzheimer’s disease (AD), are associated with low efficacy and adverse effects. M1 muscarinic acetylcholine receptors (M1 mAChRs) repr...
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Article
Activation of the GLP-1 receptor by a non-peptidic agonist
Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, including diabetes and obesity1. Structures of active receptors reveal peptide agonists engage deep within the receptor...
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Article
Open AccessCryptic pocket formation underlies allosteric modulator selectivity at muscarinic GPCRs
Allosteric modulators are highly desirable as drugs, particularly for G-protein-coupled receptor (GPCR) targets, because allosteric drugs can achieve selectivity between closely related receptors. The mechanis...
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Article
Open AccessExpression and activity of the calcitonin receptor family in a sample of primary human high-grade gliomas
Glioblastoma (GBM) is the most common and aggressive type of primary brain cancer. With median survival of less than 15 months, identification and validation of new GBM therapeutic targets is of critical impor...
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Article
Mechanisms of signalling and biased agonism in G protein-coupled receptors
G protein-coupled receptors (GPCRs) are the largest group of cell surface receptors in humans that signal in response to diverse inputs and regulate a plethora of cellular processes. Hence, they constitute one...
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Article
Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor
Calcitonin gene-related peptide (CGRP) is a widely expressed neuropeptide that has a major role in sensory neurotransmission. The CGRP receptor is a heterodimer of the calcitonin receptor-like receptor (CLR) c...
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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...
