Nat. Struct. Mol. Biol., published online 11 March 2012, doi:10.1038/nsmb.2253

Credit: LEO C. JAMES

The Rhesus macaque TRIMCyp (RhTC) antiviral protein binds and restricts multiple lentiviruses, whereas the homologous protein cyclophilin A (CypA) targets only HIV-1. Previous work showed that two mutations in RhTC gave rise to a new binding-site conformation. Caines et al. discover that RhTC adopts multiple new conformations and this structural versatility allows RhTC to target different viruses. The authors crystallized the RhTC CypA domain bound to either HIV-1 or HIV-2 capsid and observed that the two RhTC structures are substantially different. NMR analyses revealed that the loop in which the two RhTC mutations reside is no longer constrained by hydrogen bonds; it is highly mobile compared to CypA. The authors validated the role of the loop in the recognition of multiple viruses by reversing its structural flexibility. They introduced a cysteine to force the formation of a disulfide bridge, and as a result they locked the position of the loop and the conformation of the active site. Isothermal titration calorimetry and X-ray crystallography showed that the constrained RhTC lost the ability to recognize HIV-2. Reduction of the disulfide bond reversed the constraint and allowed RhTC to bind multiple viruses. This study reveals how an antiviral protein acquired an adaptable binding site and the ability to target multiple viruses.