Structural Basis for Dengue Virus Antibody Dependent Maturation

Abstract

Event Abstract Back to Event Structural basis for dengue virus antibody dependent maturation Jan K. Marzinek1 and Peter J. Bond1* 1 Bioinformatics Institute (A*STAR), Singapore Background Dengue virus (DENV) is responsible for millions of infections a year around the world. DENV is composed of an RNA genome complexed with capsid (C) proteins, which are surrounded by envelope (E) and membrane (M) proteins embedded within a lipid bilayer. In nascent viral particles, the pre-membrane (prM) protein caps the fusion loop of the E protein, making it non-fusogenic. During maturation, cleavage of prM into the M protein and release of pr leads to a conformational change in the E protein that makes it fusion-competent. Interestingly, DENV is known to be released from cells under different states of maturation. Fully immature DENV (immDENV) is non-infectious. However, its infectivity can be enhanced when DENV is targeted by host anti-prM antibodies. The molecular basis for this antibody-dependent enhancement has until recently been unknown. Methods In this work, cryo-electron microscopy (cryo-EM) structures of the immDENV:anti-prM complex at acidic and neutral pH conditions mimicking the endosomal and extracellular environments respectively were analyzed via integrative modeling and simulation approaches. Results At acidic pH, an intermediate structure of the DENV maturation pathway has been solved with fewer antibodies bound in comparison to neutral pH. Based on previously developed multiscale models of the DENV particle, we employed sets of targeted molecular dynamics (TMD) simulations in order to trigger the maturation transition at low pH. Hydrogen-deuterium exchange mass spectroscopy and Elisa measurements confirmed that the affinity of the antibody:pr complexes are stronger than those of the pr:E complexes, and the TMD simulations revealed dislodgement of antibody:pr from the E protein surface during the conformational transition due to steric clashes. Conclusion Here, we provide the detailed molecular mechanism by which anti-prM antibodies enhance maturation of DENV in the acidic endosomal environment, leading to exposure of the E protein fusion loops for subsequent endosomal membrane binding and fusion. Acknowledgements National Research Foundation: CRP Grant Number: NRF2017-CRP001-027 Keywords: Dengue virus maturation, cryo-electron microscopy, antibody, PRM, Molecular dynamic simulations Conference: International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18) “Seizing Opportunities and Addressing Challenges of Precision Medicine”, Putrajaya, Malaysia, 3 Dec - 5 Feb, 2019. Presentation Type: Oral Presentation Topic: Infectious diseases Citation: Marzinek JK and Bond PJ (2019). Structural basis for dengue virus antibody dependent maturation. Front. Pharmacol. Conference Abstract: International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18) “Seizing Opportunities and Addressing Challenges of Precision Medicine”. doi: 10.3389/conf.fphar.2018.63.00082 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 30 Sep 2018; Published Online: 17 Jan 2019. * Correspondence: Dr. Peter J Bond, Bioinformatics Institute (A*STAR), Singapore, Singapore, peterjb@bii.a-star.edu.sg Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Jan K Marzinek Peter J Bond Google Jan K Marzinek Peter J Bond Google Scholar Jan K Marzinek Peter J Bond PubMed Jan K Marzinek Peter J Bond Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.