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Sci Adv. 2017 Sep 15;3(9):e1701264. doi: 10.1126/sciadv.1701264. eCollection 2017 Sep.

CryoEM structure of MxB reveals a novel oligomerization interface critical for HIV restriction.

Author information

1
Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
2
Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
3
MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
4
Department of Physics and Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
5
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
6
Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
7
Division of Structural Biology, Henry Wellcome Building for Genomic Medicine, University of Oxford, Headington, Oxford OX3 7BN, UK.
8
Electron Bio-Imaging Centre, Diamond Light Source, Harwell Science and Innovation Campus, Didcot OX11 0DE, UK.

Abstract

Human dynamin-like, interferon-induced myxovirus resistance 2 (Mx2 or MxB) is a potent HIV-1 inhibitor. Antiviral activity requires both the amino-terminal region of MxB and protein oligomerization, each of which has eluded structural determination due to difficulties in protein preparation. We report that maltose binding protein-fused, full-length wild-type MxB purifies as oligomers and further self-assembles into helical arrays in physiological salt. Guanosine triphosphate (GTP), but not guanosine diphosphate, binding results in array disassembly, whereas subsequent GTP hydrolysis allows its reformation. Using cryo-electron microscopy (cryoEM), we determined the MxB assembly structure at 4.6 Å resolution, representing the first near-atomic resolution structure in the mammalian dynamin superfamily. The structure revealed previously described and novel MxB assembly interfaces. Mutational analyses demonstrated a critical role for one of the novel interfaces in HIV-1 restriction.

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