The retroviral surface envelope protein subunit (SU) mediates receptor binding and triggers membrane fusion by the transmembrane (TM) subunit. SU evolves rapidly under strong selective conditions, resulting in seemingly unrelated SU structures in highly divergent retroviruses. Structural modeling of the SUs of several retroviruses and related endogenous retroviral elements with AlphaFold 2 identifies a TM-proximal SU β-sandwich structure that has been conserved in the orthoretroviruses for at least 110 million years. The SU of orthoretroviruses diversified by the differential expansion of the β-sandwich core to form domains involved in virus-host interactions. The β-sandwich domain is also conserved in the SU equivalent GP1 of Ebola virus although with a significantly different orientation in the trimeric envelope protein structure relative to the β-sandwich of human immunodeficiency virus type 1 gp120, with significant evidence for divergent rather than convergent evolution. The unified structural view of orthoretroviral SU and filoviral GP1 identifies an ancient, structurally conserved, and evolvable domain underlying the structural diversity of orthoretroviral SU and filoviral GP1.

Models for orthoretroviral SU were genenerated with AlphaFold 2. A simplified version25 of Alphafold 2 run on the ColabFold server with graphical processing unit support accessible at https://colab.research.google.com/github/sokrypton/ColabFold/blob/main/AlphaFold2.ipynb was used for modeling with templates, without amber relaxation and homooligomer set to 1. Comparable models were obtained by modeling with or without templates or amber relaxation.

pLDDT scores in B-factor column 11.