Multidimensional Regulatory Mechanisms and Targeting Strategies of the eEF1 Family in RNA Virus Infection

Figures

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  Figure 1. Domain structure and functions of eEF1A. eEF1A consists of three well-characterized structural domains: domain I (residues 4–234) is responsible for GTP/GDP binding; domain II (residues 241–328) participates in aminoacyl-tRNA binding; and domain III (residues 337–462/463) is involved in actin binding.

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  Figure 2. Structural model of the eEF1B(αβγ)₃ complex and domain organization of its subunits. (A) Domain architecture of eEF1Bα (light green): comprises an N-terminal domain, linker region, CAR, and GEF domain. eEF1Bα specifically interacts with eEF1Bβ via its N-terminal domain, while its GEF domain synergistically regulates complex function. (B) Domain architecture of eEF1Bβ (dark blue): contains an N-terminal domain, LZ motif, linker region, CAR, and GEF domain. eEF1Bβ forms a stable trimeric core via its LZ motif (helical bundle), with CAR and GEF domains extending outward from the core. (C) Domain architecture of eEF1Bγ (yellow): includes an N-terminal domain, linker region, and C-terminal domain. eEF1Bγ acts as a scaffold by simultaneously binding eEF1Bβ and eEF1Bα through its N-terminal domain. (D) Overall architecture of the eEF1B(αβγ)₃ complex: subunits α, β, and γ assemble in a 1:1:1 stoichiometry, forming a functional complex with six GEF domains. The LZ-mediated β-trimer forms the structural core, while α and γ stabilize the assembly via domain-specific interactions.

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  Figure 3. Structural architecture of the eEF1H supercomplex. The eEF1H supercomplex is organized around a trimeric core formed by three eEF1Bβ subunits (dark blue), which dimerize via their LZ motifs (purple) to create a stable helical bundle. Each eEF1Bβ subunit extends a GEF domain that directly binds an eEF1A molecule (orange), while its N-terminal domain interacts with an eEF1Bγ subunit (yellow). The eEF1Bγ subunits act as structural connectors, bridging the eEF1Bβ core to three eEF1Bα subunits (light green). Each eEF1Bα binds an additional eEF1A molecule through its GEF domain, resulting in a complete assembly of the eEF1B(αβγ)₃ complex (as detailed in Figure 2) integrated with six eEF1A molecules. The final architecture positions the six eEF1A molecules around the central β-trimer core, with the GEF domains of eEF1Bα and eEF1Bβ arranged to spatially coordinate their interactions with eEF1A.

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  Figure 4. Hierarchical mapping of eEF1A−virus protein interactions and their regulatory roles across infection stages. The concentric circles (from inner to outer) illustrate: (1) regulatory effects of eEF1A on viruses (promoting or inhibiting viral infection); (2) viral proteins interacting with eEF1A; (3) names and types of viruses associated with eEF1A interactions; (4) stages of viral infection influenced by eEF1A.

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  Figure 5. Viral proteins interacting with eEF1B and their regulatory effects. The concentric circles (from inner to outer) sequentially represent: (1) types of eEF1B subunits interacting with viruses; (2) regulatory effects of eEF1B on viruses; (3) viral proteins interacting with eEF1B; (4) names and types of viruses associated with eEF1B interactions; (5) stages of viral infection influenced by eEF1B.

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  Figure 6. Mechanisms of antiviral drugs targeting the eEF1 family. (A) Plitidepsin inhibits viral protein synthesis by binding to eEF1A to block translation elongation, inducing eIF2α phosphorylation to disrupt translation initiation, and activating the Rac1–JNK1 pathway to trigger apoptosis, thereby enhancing antiviral efficacy. (B) Anisomycin inhibits viral replication by promoting the interaction between the host protein eEF1A and the chaperone HSC70, thereby inducing lysosomal degradation of eEF1A1 via the LAMP2A-dependent chaperone-mediated autophagy (CMA) pathway. (C) Oxazole-benzenesulfonamide derivatives interfere with the early-stage reverse transcription process by binding to HIV RT to block its interaction with eEF1A, without directly inhibiting RT enzymatic activity. Didemnin B suppresses the late-stage viral reverse transcription process by directly binding to eEF1A, disrupting its interaction with RT and destabilizing the RTC.