scholarly journals Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhaotong Cong ◽  
Li-Nan Chen ◽  
Honglei Ma ◽  
Qingtong Zhou ◽  
Xinyu Zou ◽  
...  
Keyword(s):  
Drug Target ◽  
Metabolic Disorders ◽  
Allosteric Modulation ◽  
Structural Basis ◽  
Allosteric Modulators ◽  
Cryo Electron Microscopy ◽  
Covalently Bonded ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Orthosteric Ligands

AbstractThe glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy enhancers of orthosteric ligands. However, the molecular details of ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric Gs. The structures reveal that compound 2 is covalently bonded to C347 at the cytoplasmic end of TM6 and triggers its outward movement in cooperation with the ECD whose N terminus penetrates into the GLP-1 binding site. This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling. Our findings offer insights into the structural basis of ago-allosterism at GLP-1R and may aid the design of better therapeutics.

scholarly journals Structural basis for the therapeutic advantage of dual and triple agonists at the human GIP, GLP-1 or GCG receptors

2021 ◽  
Author(s):  
Fenghui Zhao ◽  
Qingtong Zhou ◽  
Zhaotong Cong ◽  
Kaini Hang ◽  
Xinyu Zou ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Atomic Level ◽  
Structural Basis ◽  
Therapeutic Advantage ◽  
Cryo Electron Microscopy ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Diabetes And Obesity ◽  
Functional Versatility

Glucose homeostasis, regulated by glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon (GCG) is critical to human health. Several multi-targeting agonists at GIPR, GLP-1R or GCGR, developed to maximize metabolic benefits with reduced side-effects, are in clinical trials to treat type 2 diabetes and obesity. To elucidate the molecular mechanisms by which tirzepatide, a GIPR/GLP-1R dualagonist, and peptide 20, a GIPR/GLP-1R/GCGR triagonist, manifest their superior efficacies over monoagonist such as semaglutide, we determined cryo-electron microscopy structures of tirzepatide-bound GIPR and GLP-1R as well as peptide 20-bound GIPR, GLP-1R and GCGR The structures reveal both common and unique features for the dual and triple agonism by illustrating key interactions of clinical relevance at the atomic level. Retention of glucagon function is required to achieve such an advantage over GLP-1 monotherapy. Our findings provide valuable insights into the structural basis of functional versatility and therapeutic supremacy of tirzepatide and peptide 20.

scholarly journals A Duplexed High-Throughput Screen to Identify Allosteric Modulators of the Glucagon-Like Peptide 1 and Glucagon Receptors

2014 ◽  
Vol 19 (6) ◽  
pp. 847-858 ◽  
Author(s):  
Lindsey C. Morris ◽  
Emily L. Days ◽  
Maxine Turney ◽  
Dehui Mi ◽  
Craig W. Lindsley ◽  
...  
Keyword(s):  
High Throughput ◽  
Allosteric Modulators ◽  
High Throughput Screen ◽  
Glucagon Receptor ◽  
Three Phase ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Orally Bioavailable ◽  
Glucagon Receptors

Injectable, degradation-resistant peptide agonists for the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R), such as exenatide and liraglutide, activate the GLP-1R via a complex orthosteric-binding site and are effective therapeutics for glycemic control in type 2 diabetes. Orally bioavailable orthosteric small-molecule agonists are unlikely to be developed, whereas positive allosteric modulators (PAMs) may offer an improved therapeutic profile. We hypothesize that allosteric modulators of the GLP-1R would increase the potency and efficacy of native GLP-1 in a spatial and temporally preserved manner and/or may improve efficacy or side effects of injectable analogs. We report the design, optimization, and initial results of a duplexed high-throughput screen in which cell lines overexpressing either the GLP-1R or the glucagon receptor were coplated, loaded with a calcium-sensitive dye, and probed in a three-phase assay to identify agonists, antagonists, and potentiators of GLP-1, and potentiators of glucagon. 175,000 compounds were initially screened, and progression through secondary assays yielded 98 compounds with a variety of activities at the GLP-1R. Here, we describe five compounds possessing different patterns of modulation of the GLP-1R. These data uncover PAMs that may offer a drug-development pathway to enhancing in vivo efficacy of both endogenous GLP-1 and peptide analogs.

scholarly journals Structural basis for strand-transfer inhibitor binding to HIV intasomes

Science ◽  
2020 ◽  
Vol 367 (6479) ◽  
pp. 810-814 ◽  
Author(s):  
Dario Oliveira Passos ◽  
Min Li ◽  
Ilona K. Jóźwik ◽  
Xue Zhi Zhao ◽  
Diogo Santos-Martins ◽  
...  
Keyword(s):  
High Resolution ◽  
Drug Target ◽  
Antiretroviral Drugs ◽  
Drug Binding ◽  
Structural Basis ◽  
Strand Transfer ◽  
Cryo Electron Microscopy ◽  
Integrase Strand Transfer Inhibitors ◽  
Transfer Inhibitor ◽  
Host Chromatin

The HIV intasome is a large nucleoprotein assembly that mediates the integration of a DNA copy of the viral genome into host chromatin. Intasomes are targeted by the latest generation of antiretroviral drugs, integrase strand-transfer inhibitors (INSTIs). Challenges associated with lentiviral intasome biochemistry have hindered high-resolution structural studies of how INSTIs bind to their native drug target. Here, we present high-resolution cryo–electron microscopy structures of HIV intasomes bound to the latest generation of INSTIs. These structures highlight how small changes in the integrase active site can have notable implications for drug binding and design and provide mechanistic insights into why a leading INSTI retains efficacy against a broad spectrum of drug-resistant variants. The data have implications for expanding effective treatments available for HIV-infected individuals.

scholarly journals Positive Allosteric Modulation of the Glucagon-like Peptide-1 Receptor by Diverse Electrophiles

2016 ◽  
Vol 291 (20) ◽  
pp. 10700-10715 ◽  
Author(s):  
Ana B. Bueno ◽  
Aaron D. Showalter ◽  
David B. Wainscott ◽  
Cynthia Stutsman ◽  
Aranzazu Marín ◽  
...  
Keyword(s):  
Allosteric Modulation ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals Structure and dynamics of semaglutide and taspoglutide bound GLP-1R-Gs complexes

2021 ◽  
Author(s):  
Xin Zhang ◽  
Matthew J. Belousoff ◽  
Yi-Lynn Liang ◽  
Radostin Danev ◽  
Patrick M. Sexton ◽  
...  
Keyword(s):  
Structural Information ◽  
Protein Complexes ◽  
Binding Modes ◽  
Cryo Electron Microscopy ◽  
High Incidence ◽  
Molecular Determinants ◽  
Gs Protein ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Diabetes And Obesity

SUMMARYThe glucagon-like peptide-1 receptor (GLP-1R) regulates insulin secretion, carbohydrate metabolism and appetite, and is an important target for treatment of type II diabetes and obesity. Multiple GLP-1R agonists have entered into clinical trials, such as semaglutide, progressing to approval. Others, including taspoglutide, failed through high incidence of side-effects or insufficient efficacy. GLP-1R agonists have a broad spectrum of signalling profiles. However, molecular understanding is limited by a lack of structural information on how different GLP-1R agonists engage with the GLP-1R. In this study, we determined cryo-electron microscopy (cryo-EM) structures of GLP-1R-Gs protein complexes bound with semaglutide and taspoglutide. These revealed similar peptide binding modes to that previously observed for GLP-1. However, 3D variability analysis of the cryo-EM micrographs revealed different motions within the bound peptides and the receptor relative to when GLP-1 is bound. This work provides novel insights into the molecular determinants of peptide engagement with the GLP-1R.

scholarly journals Repositioning Dequalinium as Potent Muscarinic Allosteric Ligand by Combining Virtual Screening Campaigns and Experimental Binding Assays

2020 ◽  
Vol 21 (17) ◽  
pp. 5961
Author(s):  
Angelica Mazzolari ◽  
Silvia Gervasoni ◽  
Alessandro Pedretti ◽  
Laura Fumagalli ◽  
Rosanna Matucci ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Allosteric Modulation ◽  
Allosteric Modulators ◽  
Binding Assays ◽  
Docking Protocol ◽  
Consensus Models ◽  
Binding Cavity ◽  
Orthosteric Ligands ◽  
G Protein Coupled

Structure-based virtual screening is a truly productive repurposing approach provided that reliable target structures are available. Recent progresses in the structural resolution of the G-Protein Coupled Receptors (GPCRs) render these targets amenable for structure-based repurposing studies. Hence, the present study describes structure-based virtual screening campaigns with a view to repurposing known drugs as potential allosteric (and/or orthosteric) ligands for the hM2 muscarinic subtype which was indeed resolved in complex with an allosteric modulator thus allowing a precise identification of this binding cavity. First, a docking protocol was developed and optimized based on binding space concept and enrichment factor optimization algorithm (EFO) consensus approach by using a purposely collected database including known allosteric modulators. The so-developed consensus models were then utilized to virtually screen the DrugBank database. Based on the computational results, six promising molecules were selected and experimentally tested and four of them revealed interesting affinity data; in particular, dequalinium showed a very impressive allosteric modulation for hM2. Based on these results, a second campaign was focused on bis-cationic derivatives and allowed the identification of other two relevant hM2 ligands. Overall, the study enhances the understanding of the factors governing the hM2 allosteric modulation emphasizing the key role of ligand flexibility as well as of arrangement and delocalization of the positively charged moieties.

scholarly journals Structural Basis for Allosteric Modulation of Class B G Protein–Coupled Receptors

2020 ◽  
Vol 60 (1) ◽  
pp. 89-107 ◽  
Author(s):  
Denise Wootten ◽  
Laurence J. Miller
Keyword(s):  
G Protein ◽  
Allosteric Modulation ◽  
G Protein Coupled Receptors ◽  
Structural Basis ◽  
Allosteric Modulators ◽  
Class B ◽  
Endogenous Proteins ◽  
And Function ◽  
Agonist Ligands ◽  
G Protein Coupled

Recent advances in our understanding of the structure and function of class B G protein–coupled receptors (GPCRs) provide multiple opportunities for targeted development of allosteric modulators. Given the pleiotropic signaling patterns emanating from these receptors in response to a variety of natural agonist ligands, modulators have the potential to sculpt the responses to meet distinct needs of different groups of patients. In this review, we provide insights into how this family of GPCRs differs from the rest of the superfamily, how orthosteric agonists bind and activate these receptors, the potential for allosteric modulators to interact with various regions of these targets, and the allosteric influence of endogenous proteins on the pharmacology of these receptors, all of which are important considerations when developing new therapies.

scholarly journals Physiology and Emerging Biochemistry of the Glucagon-Like Peptide-1 Receptor

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Francis S. Willard ◽  
Kyle W. Sloop
Keyword(s):  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Receptor Occupancy ◽  
Allosteric Modulators ◽  
Three Dimensional Modeling ◽  
Dimensional Modeling ◽  
Signaling Mechanisms ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

The glucagon-like peptide-1 (GLP-1) receptor is one of the best validated therapeutic targets for the treatment of type 2 diabetes mellitus (T2DM). Over several years, the accumulation of basic, translational, and clinical research helped define the physiologic roles of GLP-1 and its receptor in regulating glucose homeostasis and energy metabolism. These efforts provided much of the foundation for pharmaceutical development of the GLP-1 receptor peptide agonists, exenatide and liraglutide, as novel medicines for patients suffering from T2DM. Now, much attention is focused on better understanding the molecular mechanisms involved in ligand induced signaling of the GLP-1 receptor. For example, advancements in biophysical and structural biology techniques are being applied in attempts to more precisely determine ligand binding and receptor occupancy characteristics at the atomic level. These efforts should better inform three-dimensional modeling of the GLP-1 receptor that will help inspire more rational approaches to identify and optimize small molecule agonists or allosteric modulators targeting the GLP-1 receptor. This article reviews GLP-1 receptor physiology with an emphasis on GLP-1 induced signaling mechanisms in order to highlight new molecular strategies that help determine desired pharmacologic characteristics for guiding development of future nonpeptide GLP-1 receptor activators.

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