Three-dimensional macromolecular structures shed critical light on biological mechanism and facilitate development of small molecule inhibitors. Clinical success of raltegravir, a potent inhibitor of HIV-1 integrase, demonstrated the utility of this viral DNA recombinase as an antiviral target. A variety of partial integrase structures reported in the past 16 years have been instrumental and very informative to the field. Nonetheless, because integrase protein fragments are unable to functionally engage the viral DNA substrate critical for strand transfer inhibitor binding, the early structures did little to materially impact drug development efforts.

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However, recent results based on prototype foamy virus integrase have fully reversed this trend, as a number of X-ray crystal structures of active integrase-DNA complexes revealed key mechanistic details and moreover established the foundation of HIV-1 IN strand transfer inhibitor action. In this review we discuss the landmarks in the progress of IN structural biology during the past 17 years. Introduction The integration of the linear viral DNA (vDNA) made during reverse transcription into a cell chromosome is one of many essential steps in the retroviral lifecycle. Integration is orchestrated by the viral integrase (IN) protein, which recognizes and acts upon the vDNA ends, catalyzing two sequential endonucleolytic reactions. Initially, IN hydrolyzes a phosphodiester at one or both 3′ ends adjacent to invariant CA sequences to unveil reactive adenosine 3′-OH groups. Then, after finding a suitable target site on chromatin in the cell nucleus, IN carries out DNA strand transfer by using the 3′-hydroxyls to cut phosphodiester bonds on opposing strands of target DNA (tDNA) across the major groove with defined spacing, which at the same time joins the vDNA ends to the chromosome. The resulting DNA recombination intermediate, with unjoined vDNA 5′ ends abutting single stranded tDNA gaps, is repaired by host cell machinery to yield the integrated provirus flanked by the sequence duplication of the double stranded tDNA cut.

See for a recent overview of retroviral DNA integration. Seminal work in the late 1980s - early 1990s revealed recombinant IN proteins possess divalent metal ion- (Mn 2+ or Mg 2+) dependent 3′ processing and DNA strand transfer activities in vitro (;;;;; ). From this onset it was evident the 288-residue HIV-1 IN was refractory to structural biology approaches due to relatively poor protein solubility, limited at ~1 mg/ml (; ). In work designed to test if HIV-1 IN worked as an enzyme, discovered a novel in vitro function, disintegration, whereby substrates modeling the DNA strand transfer reaction product could be separated into viral and tDNA components. Although disintegration activity is probably not relevant to virus infection, it was a boon for dissecting IN functionality. Retroviral IN proteins contain three or four sub-domains of variable evolutionary conservation (). The catalytic core domain (CCD) harbors a D,D-35-E amino acid sequence motif conserved among retroviral and retrotransposon INs as well as some bacterial transposase proteins (; ), and the invariant Asp and Glu residues (Asp64, Asp116, and Glu152 for HIV-1) were critical for catalysis of 3′ processing, DNA strand transfer (; ), and disintegration activities (;; ).

Isolated CCDs from HIV-1 () and avian sarcoma-leukosis virus (ASLV) () IN proteins lacked appreciable 3’ processing and DNA strand transfer activities, yet importantly were proficient at disintegration. Mixtures of certain defective HIV IN N-terminal domain (NTD) and C-terminal domain (CTD) deletion mutant proteins moreover supported 3′ processing and DNA strand transfer activities, suggesting that the protein likely functioned as a multimer and that individual IN chains could share their domains within the functional complex (;; ). Additional protein mixing experiments yielded overall similar domain organizations for Gammaretrovirus () and Spumavirus () INs (). Despite frustrations with full-length INs, these studies established the validity of structural approaches of isolated protein domains. Domain organization and secondary structural elements of representative IN proteins.