title: Active site remodeling switches HIV specificity of antiretroviral TRIMCyp.
abstract: TRIMCyps are primate antiretroviral proteins that potently inhibit HIV replication. Here we describe how rhesus macaque TRIMCyp (RhTC) has evolved to target and restrict HIV-2. We show that the ancestral cyclophilin A (CypA) domain of RhTC targets HIV-2 capsid with weak affinity, which is strongly increased in RhTC by two mutations (D66N and R69H) at the expense of HIV-1 binding. These mutations disrupt a constraining intramolecular interaction in CypA, triggering the complete restructuring (>16 A) of an active site loop. This new configuration discriminates between divergent HIV-1 and HIV-2 loop conformations mediated by capsid residue 88. Viral sensitivity to RhTC restriction can be conferred or abolished by mutating position 88. Furthermore, position 88 determines the susceptibility of naturally occurring HIV-1 sequences to restriction. Our results reveal the complex molecular, structural and thermodynamic changes that underlie the ongoing evolutionary race between virus and host.
authors.affiliation: Protein and Nucleic Acid Chemistry Division, Medical Research Council Laboratory of Molecular Biology, Cambridge, UK.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Price
authors.forename: Flavia
authors.initials: F
authors.lastname: Marzetta
authors.forename: Michael
authors.initials: M
authors.lastname: Lammers
authors.forename: Laura M J
authors.initials: LM
authors.lastname: Ylinen
authors.forename: Torsten
authors.initials: T
authors.lastname: Schaller
authors.forename: Sam J
authors.initials: SJ
authors.lastname: Wilson
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Towers
authors.forename: Leo C
authors.initials: LC
authors.lastname: James
mesh_terms: D000818:Animals; D044966:Anti-Retroviral Agents / Q000494:pharmacology*; D002213:Capsid / Q000737:chemistry; D020134:Catalytic Domain; D021984:Cyclophilin A / Q000737:chemistry; D015497:HIV-1 / Q000378:metabolism*; D015498:HIV-2 / Q000378:metabolism; D007700:Kinetics; D008253:Macaca mulatta; D008968:Molecular Conformation; D009154:Mutation; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D013816:Thermodynamics; D014764:Viral Proteins / Q000737:chemistry; D014779:Virus Replication
chemical_list: D044966:Anti-Retroviral Agents; D014764:Viral Proteins; D021984:Cyclophilin A; D019696:Peptidylprolyl Isomerase