Structures of Nef bound to AP-2 or AP-1 and host factors targeted for downregulation. Central composite structures of AP-2 and AP-1 were composed by aligning PDB IDs 6CM9, 4EMZ, 4NEE, and 6OWT. In this composite structure, Nef is bound at both the tyrosine and dileucine binding sites. The sites where Nef binds host factors CD4 (PDB ID 5NUI), CD3ζ (PDB ID 3IK5), and simian tetherin (6OWT) are indicated for the dileucine binding site of AP-2. The AP-2 β2 subunit is indicated to highlight the formation of the N-terminal β-hairpin upon binding to simian tetherin. The sites where Nef binds host factors MHC-I (PDB ID 4EMZ) and human tetherin (6CM9) are indicated for the tyrosine binding site of AP-1. All positions of the host factors were determined by aligning the Nef core of the respective PDBs to the Nef cores of PDB ID 4NEE (AP-2 interacting partners) and PDB ID 4EMZ (AP-1-interacting partners).