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

Katherine Basore, Hongming Ma, Natasha M. Kafai, Samantha Mackin, Arthur S. Kim, Christopher A. Nelson, Michael S. Diamond () and Daved H. Fremont ()
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Katherine Basore: Washington University School of Medicine
Hongming Ma: Washington University School of Medicine
Natasha M. Kafai: Washington University School of Medicine
Samantha Mackin: Washington University School of Medicine
Arthur S. Kim: Washington University School of Medicine
Christopher A. Nelson: Washington University School of Medicine
Michael S. Diamond: Washington University School of Medicine
Daved H. Fremont: Washington University School of Medicine

Nature, 2021, vol. 598, issue 7882, 672-676

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03963-9

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