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Structural Basis for Functional Tetramerization of Lentiviral Integrase

DOI: 10.1371/journal.ppat.1000515 DOI Help
PMID: 19609359 PMID Help

Authors: Stephen Hare (Imperial College London) , Francesca Di Nunzio (Dana-Farber Cancer Institute, Boston) , Alfred Labeja (Imperial College London) , Jimin Wang (Yale University) , Alan Engelmann (Dana-Farber Cancer Institute, Boston) , Peter Cherepanov (Imperial College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Plos Pathogens , VOL 5(7)

State: Published (Approved)
Published: July 2009

Open Access Open Access

Abstract: Experimental evidence suggests that a tetramer of integrase (IN) is the protagonist of the concerted strand transfer reaction, whereby both ends of retroviral DNA are inserted into a host cell chromosome. Herein we present two crystal structures containing the N-terminal and the catalytic core domains of maedi-visna virus IN in complex with the IN binding domain of the common lentiviral integration co-factor LEDGF. The structures reveal that the dimer-of-dimers architecture of the IN tetramer is stabilized by swapping N-terminal domains between the inner pair of monomers poised to execute catalytic function. Comparison of four independent IN tetramers in our crystal structures elucidate the basis for the closure of the highly flexible dimer-dimer interface, allowing us to model how a pair of active sites become situated for concerted integration. Using a range of complementary approaches, we demonstrate that the dimer-dimer interface is essential for HIV-1 IN tetramerization, concerted integration in vitro, and virus infectivity. Our structures moreover highlight adaptable changes at the interfaces of individual IN dimers that allow divergent lentiviruses to utilize a highly-conserved, common integration co-factor

Journal Keywords: X-Ray; HIV; HIV-1; Integrases; Intercellular; Models; Molecular; Mutation; Protein; Viral; Visna-maedi; vpr; Human Immunodeficiency Virus

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography