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Proc Natl Acad Sci U S A. 2014 Jul 1;111(26):9609-14. doi: 10.1073/pnas.1402448111. Epub 2014 Jun 16.

Structural studies of postentry restriction factors reveal antiparallel dimers that enable avid binding to the HIV-1 capsid lattice.

Author information

  • 1Divisions of Molecular Structure,School of Biological Sciences, University of Auckland, Auckland, New Zealand; and
  • 2Divisions of Molecular Structure.
  • 3Physical Biochemistry, and.
  • 4School of Biological Sciences, University of Auckland, Auckland, New Zealand; and.
  • 5Virology, National Institute for Medical Research, London NW7 1AA, United Kingdom;
  • 6Virology, National Institute for Medical Research, London NW7 1AA, United Kingdom;Faculty of Medicine, Imperial College London, London SW7 2AZ, United Kingdom.
  • 7Divisions of Molecular Structure,


Restriction factors (RFs) form important components of host defenses to retroviral infection. The Fv1, Trim5α, and TrimCyp RFs contain N-terminal dimerization and C-terminal specificity domains that target assembled retroviral capsid (CA) proteins enclosing the viral core. However, the molecular detail of the interaction between RFs and their CA targets is unknown. Therefore, we have determined the crystal structure of the B-box and coiled-coil (BCC) region from Trim5α and used small-angle X-ray scattering to examine the solution structure of Trim5α BCC, the dimerization domain of Fv1 (Fv1Ntd), and the hybrid restriction factor Fv1Cyp comprising Fv1NtD fused to the HIV-1 binding protein Cyclophilin A (CypA). These data reveal that coiled-coil regions of Fv1 and Trim5α form extended antiparallel dimers. In Fv1Cyp, two CypA moieties are located at opposing ends, creating a molecule with a dumbbell appearance. In Trim5α, the B-boxes are located at either end of the coiled-coil, held in place by interactions with a helical motif from the L2 region of the opposing monomer. A comparative analysis of Fv1Cyp and CypA binding to a preformed HIV-1 CA lattice reveals how RF dimerization enhances the affinity of interaction through avidity effects. We conclude that the antiparallel organization of the NtD regions of Fv1 and Trim5α dimers correctly positions C-terminal specificity and N-terminal effector domains and facilitates stable binding to adjacent CA hexamers in viral cores.


MLV; SAXS; X-ray crystallography; retrovirus

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