Structures of HCMV Trimer reveal the basis for receptor recognition and cell entry.
TL;DR: In this article, the authors determine three cryogenic electron microscopy (cryo-EM) structures of the trimer and the details of its interactions with four binding partners: the receptor proteins PDGFRα and TGFβR3 as well as two broadly neutralizing antibodies.
About: This article is published in Cell.The article was published on 2021-03-04. It has received 27 citations till now. The article focuses on the topics: Growth factor receptor & Population.
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TL;DR: In this article , the authors describe advances in antibody discovery and engineering that have led to the development of mAbs for use against infections caused by viruses including SARS-CoV-2, respiratory syncytial virus (RSV), Ebola virus (EBOV), human cytomegalovirus (HCMV), and influenza.
Abstract: Monoclonal antibodies (mAbs) are appealing as potential therapeutics and prophylactics for viral infections owing to characteristics such as their high specificity and their ability to enhance immune responses. Furthermore, antibody engineering can be used to strengthen effector function and prolong mAb half-life, and advances in structural biology have enabled the selection and optimization of potent neutralizing mAbs through identification of vulnerable regions in viral proteins, which can also be relevant for vaccine design. The COVID-19 pandemic has stimulated extensive efforts to develop neutralizing mAbs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with several mAbs now having received authorization for emergency use, providing not just an important component of strategies to combat COVID-19 but also a boost to efforts to harness mAbs in therapeutic and preventive settings for other infectious diseases. Here, we describe advances in antibody discovery and engineering that have led to the development of mAbs for use against infections caused by viruses including SARS-CoV-2, respiratory syncytial virus (RSV), Ebola virus (EBOV), human cytomegalovirus (HCMV) and influenza. We also discuss the rationale for moving from empirical to structure-guided strategies in vaccine development, based on identifying optimal candidate antigens and vulnerable regions within them that can be targeted by antibodies to result in a strong protective immune response. Monoclonal antibodies (mAbs) are appealing as potential therapeutics and prophylactics for viral infections. This Review describes advances in antibody discovery and engineering that have led to the development of mAbs that target viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respiratory syncytial virus and Ebola virus, and also considers the implications for vaccine development.
35 citations
TL;DR: This review focused on the PDGF/PDGFR pathway as key signaling molecules in the development of tissue fibrosis and highlighted the possible role of stimulatory anti- PDGFRα autoantibodies in the pathogenesis of SSc.
Abstract: Systemic sclerosis (SSc) is a clinically heterogeneous disorder of the connective tissue characterized by vascular alterations, immune/inflammatory manifestations, and organ fibrosis. SSc pathogenesis is complex and still poorly understood. Therefore, effective therapies are lacking and remain nonspecific and limited to disease symptoms. In the last few years, many molecular and cellular mediators of SSc fibrosis have been described, providing new potential options for targeted therapies. In this review: (i) we focused on the PDGF/PDGFR pathway as key signaling molecules in the development of tissue fibrosis; (ii) we highlighted the possible role of stimulatory anti-PDGFRα autoantibodies in the pathogenesis of SSc; (iii) we reported the most promising PDGF/PDGFR targeting therapies.
10 citations
TL;DR: Deep mutagenesis is a powerful tool for understanding the sequence diversity available to viruses for adaptation in a laboratory setting as discussed by the authors, which generally involves tracking an in vitro selection of protein sequence variants with deep sequencing to map mutational effects based on changes in sequence abundance.
Abstract: Deep mutational scanning or deep mutagenesis is a powerful tool for understanding the sequence diversity available to viruses for adaptation in a laboratory setting. It generally involves tracking an in vitro selection of protein sequence variants with deep sequencing to map mutational effects based on changes in sequence abundance. Coupled with any of a number of selection strategies, deep mutagenesis can explore the mutational diversity available to viral glycoproteins, which mediate critical roles in cell entry and are exposed to the humoral arm of the host immune response. Mutational landscapes of viral glycoproteins for host cell attachment and membrane fusion reveal extensive epistasis and potential escape mutations to neutralizing antibodies or other therapeutics, as well as aiding in the design of optimized immunogens for eliciting broadly protective immunity. While less explored, deep mutational scans of host receptors further assist in understanding virus-host protein interactions. Critical residues on the host receptors for engaging with viral spikes are readily identified and may help with structural modeling. Furthermore, mutations may be found for engineering soluble decoy receptors as neutralizing agents that specifically bind viral targets with tight affinity and limited potential for viral escape. By untangling the complexities of how sequence contributes to viral glycoprotein and host receptor interactions, deep mutational scanning is impacting ideas and strategies at multiple levels for combatting circulating and emergent virus strains.
9 citations
TL;DR: It is proposed that the intrinsic structural plasticity of gH/gL enables it to function as a signal integration machine that can accept diverse regulatory inputs and convert them into a “trigger” signal that activates the fusogenic ability of gB.
Abstract: Herpesviruses are enveloped, double-stranded DNA viruses that infect a variety of hosts across the animal kingdom. Nine of these establish lifelong infections in humans, for which there are no cures and few vaccine or treatment options. Like all enveloped viruses, herpesviruses enter cells by fusing their lipid envelopes with a host cell membrane. Uniquely, herpesviruses distribute the functions of receptor engagement and membrane fusion across a diverse cast of glycoproteins. Two glycoprotein complexes are conserved throughout the three herpesvirus subfamilies: the trimeric gB that functions as a membrane fusogen and the heterodimeric gH/gL, the role of which is less clearly defined. Here, we highlight the conserved and divergent functions of gH/gL across the three subfamilies of human herpesviruses by comparing its interactions with a broad range of accessory viral proteins, host cell receptors, and neutralizing or inhibitory antibodies. We propose that the intrinsic structural plasticity of gH/gL enables it to function as a signal integration machine that can accept diverse regulatory inputs and convert them into a “trigger” signal that activates the fusogenic ability of gB.
8 citations
TL;DR: The structures of Pentamer bound to neuropilin 2 (NRP2) and a set of potent neutralizing antibodies against HCMV are determined and thrombomodulin (THBD) is identified as a functional H CMV receptor and the structures of the Pentamer-THBD complex are determined.
Abstract: Human cytomegalovirus (HCMV) represents the viral leading cause of congenital birth defects and uses the gH/gL/UL128-130-131A complex (Pentamer) to enter different cell types, including epithelial and endothelial cells. Upon infection, Pentamer elicits the most potent neutralizing response against HCMV, representing a key vaccine candidate. Despite its relevance, the structural basis for Pentamer receptor recognition and antibody neutralization is largely unknown. Here, we determine the structures of Pentamer bound to neuropilin 2 (NRP2) and a set of potent neutralizing antibodies against HCMV. Moreover, we identify thrombomodulin (THBD) as a functional HCMV receptor and determine the structures of the Pentamer-THBD complex. Unexpectedly, both NRP2 and THBD also promote dimerization of Pentamer. Our results provide a framework for understanding HCMV receptor engagement, cell entry, antibody neutralization, and outline strategies for antiviral therapies against HCMV.
8 citations
References
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TL;DR: Coot is a molecular-graphics program designed to assist in the building of protein and other macromolecular models and the current state of development and available features are presented.
Abstract: Coot is a molecular-graphics application for model building and validation of biological macromolecules. The program displays electron-density maps and atomic models and allows model manipulations such as idealization, real-space refinement, manual rotation/translation, rigid-body fitting, ligand search, solvation, mutations, rotamers and Ramachandran idealization. Furthermore, tools are provided for model validation as well as interfaces to external programs for refinement, validation and graphics. The software is designed to be easy to learn for novice users, which is achieved by ensuring that tools for common tasks are `discoverable' through familiar user-interface elements (menus and toolbars) or by intuitive behaviour (mouse controls). Recent developments have focused on providing tools for expert users, with customisable key bindings, extensions and an extensive scripting interface. The software is under rapid development, but has already achieved very widespread use within the crystallographic community. The current state of the software is presented, with a description of the facilities available and of some of the underlying methods employed.
22,053 citations
TL;DR: A new program called Clustal Omega is described, which can align virtually any number of protein sequences quickly and that delivers accurate alignments, and which outperforms other packages in terms of execution time and quality.
Abstract: Multiple sequence alignments are fundamental to many sequence analysis methods. Most alignments are computed using the progressive alignment heuristic. These methods are starting to become a bottleneck in some analysis pipelines when faced with data sets of the size of many thousands of sequences. Some methods allow computation of larger data sets while sacrificing quality, and others produce high-quality alignments, but scale badly with the number of sequences. In this paper, we describe a new program called Clustal Omega, which can align virtually any number of protein sequences quickly and that delivers accurate alignments. The accuracy of the package on smaller test cases is similar to that of the high-quality aligners. On larger data sets, Clustal Omega outperforms other packages in terms of execution time and quality. Clustal Omega also has powerful features for adding sequences to and exploiting information in existing alignments, making use of the vast amount of precomputed information in public databases like Pfam.
12,489 citations
TL;DR: Jalview 2 is a system for interactive WYSIWYG editing, analysis and annotation of multiple sequence alignments that employs web services for sequence alignment, secondary structure prediction and the retrieval of alignments, sequences, annotation and structures from public databases and any DAS 1.53 compliant sequence or annotation server.
Abstract: Summary: Jalview Version 2 is a system for interactive WYSIWYG editing, analysis and annotation of multiple sequence alignments. Core features include keyboard and mouse-based editing, multiple views and alignment overviews, and linked structure display with Jmol. Jalview 2 is available in two forms: a lightweight Java applet for use in web applications, and a powerful desktop application that employs web services for sequence alignment, secondary structure prediction and the retrieval of alignments, sequences, annotation and structures from public databases and any DAS 1.53 compliant sequence or annotation server.
Availability: The Jalview 2 Desktop application and JalviewLite applet are made freely available under the GPL, and can be downloaded from www.jalview.org
Contact: g.j.barton@dundee.ac.uk
7,926 citations
TL;DR: Understanding of the complex signaling networks downstream from RTKs and how alterations in these networks are translated into cellular responses provides an important context for therapeutically countering the effects of pathogenic RTK mutations in cancer and other diseases.
7,056 citations
TL;DR: MotionCor2 software corrects for beam-induced sample motion, improving the resolution of cryo-EM reconstructions.
Abstract: MotionCor2 software corrects for beam-induced sample motion, improving the resolution of cryo-EM reconstructions.
5,491 citations