المؤلفون: Sarah J. Piper, Giuseppe Deganutti, Jessica Lu, Peishen Zhao, Yi-Lynn Liang, Yao Lu, Madeleine M. Fletcher, Mohammed Akhter Hossain, Arthur Christopoulos, Christopher A. Reynolds, Radostin Danev, Patrick M. Sexton, Denise Wootten

المصدر: Nature Communications, Vol 13, Iss 1, Pp 1-20 (2022)

مصطلحات موضوعية: Science

الوصف: Previously, peptide selectivity in the VPAC receptor family of GPCRs was poorly understood. Here, authors combine cryo-EM and MD data to understand binding and selectivity of VPAC1R and PAC1R peptide agonists that can guide future drug development.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/f2ad6a82f21b446eaee66d37613979d6Test

المؤلفون: Mark J. Wall, Emily Hill, Robert Huckstepp, Kerry Barkan, Giuseppe Deganutti, Michele Leuenberger, Barbara Preti, Ian Winfield, Sabrina Carvalho, Anna Suchankova, Haifeng Wei, Dewi Safitri, Xianglin Huang, Wendy Imlach, Circe La Mache, Eve Dean, Cherise Hume, Stephanie Hayward, Jess Oliver, Fei-Yue Zhao, David Spanswick, Christopher A. Reynolds, Martin Lochner, Graham Ladds, Bruno G. Frenguelli

المصدر: Nature Communications, Vol 13, Iss 1, Pp 1-22 (2022)

مصطلحات موضوعية: Science

الوصف: Wall et al. describe the selective activation of an adenosine A1 receptor-mediated intracellular pathway that provides potent analgesia in the absence of sedation or cardiorespiratory depression, paving the way for novel medicines based on the far-reaching concept of selective Gα agonism.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/248fd0638f5942beb0219612bf9fe670Test

المؤلفون: Giuseppe Deganutti, Yi-Lynn Liang, Xin Zhang, Maryam Khoshouei, Lachlan Clydesdale, Matthew J. Belousoff, Hari Venugopal, Tin T. Truong, Alisa Glukhova, Andrew N. Keller, Karen J. Gregory, Katie Leach, Arthur Christopoulos, Radostin Danev, Christopher A. Reynolds, Peishen Zhao, Patrick M. Sexton, Denise Wootten

المصدر: Nature Communications, Vol 13, Iss 1, Pp 1-18 (2022)

مصطلحات موضوعية: Science

الوصف: The glucagon-like peptide-1 receptor (GLP-1R) can be targeted in the treatment of diabetes, obesity and other metabolic disorders. Here, the authors assess the molecular mechanisms of peptide agonists binding to GLP-1R and the responses elucidated by these ligands, including distinct kinetics of G protein activation.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/8f7e8894b23a4f8eb32f5d2c26ccefc6Test

المؤلفون: Ludovico Pipitò, Christopher A. Reynolds, Giuseppe Deganutti

المصدر: Viruses, Vol 14, Iss 12, p 2789 (2022)

مصطلحات موضوعية: SARS-CoV-2, spike protein, molecular dynamics, fragment-based drug discovery, Microbiology, QR1-502

الوصف: The spike protein is key to SARS-CoV-2 high infectivity because it facilitates the receptor binding domain (RBD) encounter with ACE2. As targeting subunit S1 has not yet delivered an ACE2-binding inhibitor, we have assessed the druggability of the conserved segment of the spike protein stalk within subunit S2 by means of an integrated computational approach that combines the molecular docking of an optimized library of fragments with high-throughput molecular dynamics simulations. The high propensity of the spike protein to mutate in key regions that are responsible for the recognition of the human angiotensin-converting enzyme 2 (hACE2) or for the recognition of antibodies, has made subunit S1 of the spike protein difficult to target. Despite the inherent flexibility of the stalk region, our results suggest two hidden interhelical binding sites, whose accessibility is only partially hampered by glycan residues.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1999-4915/14/12/2789Test; https://doaj.org/toc/1999-4915Test

الوصول الحر: https://doaj.org/article/66516667fc8640f98af810ad53ae1ba6Test

المؤلفون: Maoqing Dong, Giuseppe Deganutti, Sarah J. Piper, Yi-Lynn Liang, Maryam Khoshouei, Matthew J. Belousoff, Kaleeckal G. Harikumar, Christopher A. Reynolds, Alisa Glukhova, Sebastian G. B. Furness, Arthur Christopoulos, Radostin Danev, Denise Wootten, Patrick M. Sexton, Laurence J. Miller

المصدر: Nature Communications, Vol 11, Iss 1, Pp 1-17 (2020)

مصطلحات موضوعية: Science

الوصف: The class B secretin GPCR (SecR) has broad physiological effects, with target potential for treatment of metabolic and cardiovascular disease. Here, authors present a cryo-EM structure and biochemical studies of secretin binding to the SecR:Gs complex which show that interactions between peptide and receptor were dynamic.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/35d3a9f45d2f49f5b92ff1e2f30c175aTest

المؤلفون: Ian Winfield, Kerry Barkan, Sarah Routledge, Nathan J. Robertson, Matthew Harris, Ali Jazayeri, John Simms, Christopher A. Reynolds, David R. Poyner, Graham Ladds

المصدر: Frontiers in Endocrinology, Vol 12 (2022)

مصطلحات موضوعية: GPCRs, signaling bias, CLR, RAMPs, mutagenesis, Diseases of the endocrine glands. Clinical endocrinology, RC648-665

الوصف: The first intracellular loop (ICL1) of G protein-coupled receptors (GPCRs) has received little attention, although there is evidence that, with the 8th helix (H8), it is involved in early conformational changes following receptor activation as well as contacting the G protein β subunit. In class B1 GPCRs, the distal part of ICL1 contains a conserved R12.48KLRCxR2.46b motif that extends into the base of the second transmembrane helix; this is weakly conserved as a [R/H]12.48KL[R/H] motif in class A GPCRs. In the current study, the role of ICL1 and H8 in signaling through cAMP, iCa2+ and ERK1/2 has been examined in two class B1 GPCRs, using mutagenesis and molecular dynamics. Mutations throughout ICL1 can either enhance or disrupt cAMP production by CGRP at the CGRP receptor. Alanine mutagenesis identified subtle differences with regard elevation of iCa2+, with the distal end of the loop being particularly sensitive. ERK1/2 activation displayed little sensitivity to ICL1 mutation. A broadly similar pattern was observed with the glucagon receptor, although there were differences in significance of individual residues. Extending the study revealed that at the CRF1 receptor, an insertion in ICL1 switched signaling bias between iCa2+ and cAMP. Molecular dynamics suggested that changes in ICL1 altered the conformation of ICL2 and the H8/TM7 junction (ICL4). For H8, alanine mutagenesis showed the importance of E3908.49b for all three signal transduction pathways, for the CGRP receptor, but mutations of other residues largely just altered ERK1/2 activation. Thus, ICL1 may modulate GPCR bias via interactions with ICL2, ICL4 and the Gβ subunit.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fendo.2021.792912/fullTest; https://doaj.org/toc/1664-2392Test

الوصول الحر: https://doaj.org/article/52f71ab3e9e546068dc01614028b312bTest

المؤلفون: Phil Pickford, Maria Lucey, Roxana-Maria Rujan, Emma Rose McGlone, Stavroula Bitsi, Fiona B. Ashford, Ivan R. Corrêa, David J. Hodson, Alejandra Tomas, Giuseppe Deganutti, Christopher A. Reynolds, Bryn M. Owen, Tricia M. Tan, James Minnion, Ben Jones, Stephen R. Bloom

المصدر: Molecular Metabolism, Vol 51, Iss , Pp 101242- (2021)

مصطلحات موضوعية: GLP-1, Glucagon, Oxyntomodulin, Biased agonism, Partial agonism, β-arrestin, Internal medicine, RC31-1245

الوصف: Objective: Glucagon-like peptide-1 and glucagon receptor (GLP-1R/GCGR) co-agonism can maximise weight loss and improve glycaemic control in type 2 diabetes and obesity. In this study, we investigated the cellular and metabolic effects of modulating the balance between G protein and β-arrestin-2 recruitment at GLP-1R and GCGR using oxyntomodulin (OXM)-derived co-agonists. This strategy has been previously shown to improve the duration of action of GLP-1R mono-agonists by reducing target desensitisation and downregulation. Methods: Dipeptidyl dipeptidase-4 (DPP-4)-resistant OXM analogues were generated and assessed for a variety of cellular readouts. Molecular dynamic simulations were used to gain insights into the molecular interactions involved. In vivo studies were performed in mice to identify the effects on glucose homeostasis and weight loss. Results: Ligand-specific reductions in β-arrestin-2 recruitment were associated with slower GLP-1R internalisation and prolonged glucose-lowering action in vivo. The putative benefits of GCGR agonism were retained, with equivalent weight loss compared to the GLP-1R mono-agonist liraglutide despite a lesser degree of food intake suppression. The compounds tested showed only a minor degree of biased agonism between G protein and β-arrestin-2 recruitment at both receptors and were best classified as partial agonists for the two pathways measured. Conclusions: Diminishing β-arrestin-2 recruitment may be an effective way to increase the therapeutic efficacy of GLP-1R/GCGR co-agonists. These benefits can be achieved by partial rather than biased agonism.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2212877821000879Test; https://doaj.org/toc/2212-8778Test

الوصول الحر: https://doaj.org/article/81eb48b9c1554fad855b7b0e36385ffcTest

المؤلفون: Giuseppe Deganutti, Silvia Atanasio, Roxana-Maria Rujan, Patrick M. Sexton, Denise Wootten, Christopher A. Reynolds

المصدر: Frontiers in Molecular Biosciences, Vol 8 (2021)

مصطلحات موضوعية: GPCR, CGRPR, CGRP, telcagepant, binding, molecular dynamics, Biology (General), QH301-705.5

الوصف: Class B1 G protein-coupled receptors (GPCRs) are important targets for many diseases, including cancer, diabetes, and heart disease. All the approved drugs for this receptor family are peptides that mimic the endogenous activating hormones. An understanding of how agonists bind and activate class B1 GPCRs is fundamental for the development of therapeutic small molecules. We combined supervised molecular dynamics (SuMD) and classic molecular dynamics (cMD) simulations to study the binding of the calcitonin gene-related peptide (CGRP) to the CGRP receptor (CGRPR). We also evaluated the association and dissociation of the antagonist telcagepant from the extracellular domain (ECD) of CGRPR and the water network perturbation upon binding. This study, which represents the first example of dynamic docking of a class B1 GPCR peptide, delivers insights on several aspects of ligand binding to CGRPR, expanding understanding of the role of the ECD and the receptor-activity modifying protein 1 (RAMP1) on agonist selectivity.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fmolb.2021.720561/fullTest; https://doaj.org/toc/2296-889XTest

الوصول الحر: https://doaj.org/article/d348c6f0e82d477487b7b314deab29b4Test

المؤلفون: Ludovico Pipitò, Christopher A. Reynolds, Juan Carlos Mobarec, Owen Vickery, Giuseppe Deganutti

المصدر: Biomolecules, Vol 12, Iss 11, p 1607 (2022)

مصطلحات موضوعية: SARS-CoV-2, spike protein ACE-2, molecular dynamics, supervised molecular dynamics, binding pathway, Microbiology, QR1-502

الوصف: After the SARS-CoV-2 Wuhan variant that gave rise to the pandemic, other variants named Delta, Omicron, and Omicron-2 sequentially became prevalent, with mutations spread around the viral genome, including on the spike (S) protein; in order to understand the resultant in gains in infectivity, we interrogated in silico both the equilibrium binding and the binding pathway of the virus’ receptor-binding domain (RBD) to the angiotensin-converting enzyme 2 (ACE2) receptor. We interrogated the molecular recognition between the RBD of different variants and ACE2 through supervised molecular dynamics (SuMD) and classic molecular dynamics (MD) simulations to address the effect of mutations on the possible S protein binding pathways. Our results indicate that compensation between binding pathway efficiency and stability of the complex exists for the Omicron BA.1 receptor binding domain, while Omicron BA.2′s mutations putatively improved the dynamic recognition of the ACE2 receptor, suggesting an evolutionary advantage over the previous strains.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2218-273X/12/11/1607Test; https://doaj.org/toc/2218-273XTest

الوصول الحر: https://doaj.org/article/06893b8b736a45a8894b7152a92715d3Test

المؤلفون: Payton E. Rodman, Christopher S. Reynolds

المصدر: The Astrophysical Journal, Vol 960, Iss 2, p 97 (2024)

مصطلحات موضوعية: Accretion, Black hole physics, Magnetic fields, Astrophysics, QB460-466

الوصف: We present the results from a pair of high-resolution, long-timescale (∼10 ^5 GM / c ^3 ), global, three-dimensional magnetohydrodynamical accretion disk simulations with differing initial magnetic plasma β in order to study the effects of the initial toroidal field strength on the production of a large-scale poloidal field. We initialize our disks in approximate equilibrium with purely toroidal magnetic fields of strength β _0 = 5 and 200. We also perform a limited resolution study. We find that simulations of differing field strengths diverge early in their evolution and remain distinct over the time studied, indicating that the initial magnetic conditions leave a persistent imprint in our simulations. Neither simulation enters the magnetically arrested disk regime. Both simulations are able to produce poloidal fields from initially toroidal fields, with the β _0 = 5 simulation evolving clear signs of a large-scale poloidal field. We make a cautionary note that computational artifacts in the form of large-scale vortices may be introduced in the combination of initially weak field and disk-internal mesh refinement boundaries, as evidenced by the production of an m = 1 mode overdensity in the weak field simulation. Our results demonstrate that the initial toroidal field strength plays a vital role in the simulated disk evolution for the models studied.

العلاقة: https://doi.org/10.3847/1538-4357/ad0384Test; https://doaj.org/toc/1538-4357Test; https://doaj.org/article/24c19b24db5b4e30ae25516a04b77a47Test

الإتاحة: https://doi.org/10.3847/1538-4357/ad0384Test
https://doaj.org/article/24c19b24db5b4e30ae25516a04b77a47Test