8FE3

Structure of dengue virus (DENV2) in complex with prM12, an anti-PrM monoclonal antibody

Summary for 8FE3

• Entry DOI: 10.2210/pdb8fe3/pdb
• EMDB information: 29020
• Descriptor: prM12 Fab Heavy Chain, prM12 Fab Light Chain, Envelope protein E, ... (4 entities in total)
• Functional Keywords: denv, flavivirus, prm antibody, prm12, virus-immune system complex, virus/immune system
• Biological source: Mus musculus (mouse); More
• Total number of polymer chains: 12
• Total formula weight: 303904.19

Authors

Dowd, A.D.,Sirohi, D.,Speer, S.,Mukherjee, S.,Govero, J.,Aleshnick, M.,Larman, B.,Sukupolvi-Petty, S.,Sevvana, M.,Miller, A.S.,Klose, T.,Zheng, A.,Kielian, M.,Kuhn, R.J.,Diamond, M.S.,Pierson, T.C. (deposition date: 2022-12-05, release date: 2023-02-01, Last modification date: 2024-06-19)

Primary citation

A Dowd, K.,Sirohi, D.,D Speer, S.,VanBlargan, L.A.,Chen, R.E.,Mukherjee, S.,Whitener, B.M.,Govero, J.,Aleshnick, M.,Larman, B.,Sukupolvi-Petty, S.,Sevvana, M.,Miller, A.S.,Klose, T.,Zheng, A.,Koenig, S.,Kielian, M.,Kuhn, R.J.,Diamond, M.S.,Pierson, T.C.
prM-reactive antibodies reveal a role for partially mature virions in dengue virus pathogenesis.
Proc.Natl.Acad.Sci.USA, 120:e2218899120-e2218899120, 2023

PubMed Abstract: Cleavage of the flavivirus premembrane (prM) structural protein during maturation can be inefficient. The contribution of partially mature flavivirus virions that retain uncleaved prM to pathogenesis during primary infection is unknown. To investigate this question, we characterized the functional properties of newly-generated dengue virus (DENV) prM-reactive monoclonal antibodies (mAbs) in vitro and using a mouse model of DENV disease. Anti-prM mAbs neutralized DENV infection in a virion maturation state-dependent manner. Alanine scanning mutagenesis and cryoelectron microscopy of anti-prM mAbs in complex with immature DENV defined two modes of attachment to a single antigenic site. In vivo, passive transfer of intact anti-prM mAbs resulted in an antibody-dependent enhancement of disease. However, protection against DENV-induced lethality was observed when the transferred mAbs were genetically modified to inhibit their ability to interact with Fcγ receptors. These data establish that in addition to mature forms of the virus, partially mature infectious prM virions can also contribute to pathogenesis during primary DENV infections.

PubMed: 36638211
DOI: 10.1073/pnas.2218899120

Experimental method

ELECTRON MICROSCOPY (10.2 Å)