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The activity-regulated cytoskeleton-associated protein, Arc, is highly expressed in neuronal dendrites and is involved in synaptic scaling and plasticity. Arc exhibits homology to the capsid-forming Gag proteins from retroviruses and can encapsulate its own mRNA and transport it to neighboring neurons. However, the molecular events that lead to the assembly of Arc capsids and how the capsid formation is regulated are not known. Here we show that the capsid domain of Arc may transiently form homogeneous oligomers of similar size as capsids formed by full-length Arc. We determined a high-resolution structure of the monomeric Arc capsid domain and mapped the initial structural change in the oligomerization process to the N-terminal part of the capsid domain. Peptide ligands from the NMDA receptor subunits inhibit oligomerization, which suggests that Arc's ability to transfer mRNA between cells may be regulated by protein-protein interactions at the synapse. • The Arc capsid domain has a rigid bilobar structure • The N-terminal subdomain exists in an alternative conformation • Arc CA binds both the GluN2A and GluN2B NMDA receptor subunits • Ligand binding inhibits temperature-induced oligomerization of the Arc CA domain Arc is a domesticated viral protein expressed in neurons and regulates processes underlying cognition and memory consolidation. Here, Nielsen et al. characterize the structure and dynamics of the capsid homology domain of Arc, and demonstrate that Arc interacts directly with several neuroreceptors and that these interactions interfere with domain oligomerization. [ABSTRACT FROM AUTHOR]