Structure of Venezuelan equine encephalitis virus in complex with the LDLRAD3 receptor

Nature. 2021 Oct;598(7882):672-676. doi: 10.1038/s41586-021-03963-9.

Katherine Basore ¹, Hongming Ma ², Natasha M Kafai ¹ ², Samantha Mackin ¹ ², Arthur S Kim ¹ ², Christopher A Nelson ¹, Michael S Diamond ³ ⁴ ⁵ ⁶, Daved H Fremont ⁷ ⁸ ⁹ ¹⁰

Affiliations

1 Department of Pathology & Immunology, Washington University School of Medicine, St Louis, MO, USA.
2 Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
3 Department of Pathology & Immunology, Washington University School of Medicine, St Louis, MO, USA. [email protected].
4 Department of Medicine, Washington University School of Medicine, St Louis, MO, USA. [email protected].
5 Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA. [email protected].
6 The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St Louis, MO, USA. [email protected].
7 Department of Pathology & Immunology, Washington University School of Medicine, St Louis, MO, USA. [email protected].
8 Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA. [email protected].
9 The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St Louis, MO, USA. [email protected].
10 Department of Biochemistry & Molecular Biophysics, Washington University School of Medicine, St Louis, MO, USA. [email protected].

PMID: 34646020 DOI: 10.1038/s41586-021-03963-9

Abstract

LDLRAD3 is a recently defined attachment and entry receptor for Venezuelan equine encephalitis virus (VEEV)¹, a New World alphavirus that causes severe Neurological Disease in humans. Here we present near-atomic-resolution cryo-electron microscopy reconstructions of VEEV virus-like particles alone and in a complex with the ectodomains of LDLRAD3. Domain 1 of LDLRAD3 is a low-density lipoprotein receptor type-A module that binds to VEEV by wedging into a cleft created by two adjacent E2-E1 heterodimers in one trimeric spike, and engages domains A and B of E2 and the fusion loop in E1. Atomic modelling of this interface is supported by mutagenesis and anti-VEEV antibody binding competition assays. Notably, VEEV engages LDLRAD3 in a manner that is similar to the way that arthritogenic alphaviruses bind to the structurally unrelated MXRA8 receptor, but with a much smaller interface. These studies further elucidate the structural basis of alphavirus-receptor interactions, which could inform the development of therapies to mitigate Infection and disease against multiple members of this family.

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