Structural basis for dengue virus antibody dependent maturation
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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
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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