Abstract
Integrase (IN) is a retroviral enzyme that catalyzes the insertion of viral DNA (vDNA) into host chromosomal DNA, which is necessary for efficient viral replication. The crystal structure of prototype foamy virus IN bound to cognate vDNA ends, a complex referred to as the intasome, has recently been resolved. Structure analysis of the intasome revealed a tetramer structure of IN that was required for its catalytic function, and also showed the inhibitory mechanism of the IN inhibitor. Genetic analysis of IN has revealed additional non-enzymatic roles during viral replication cycles at several steps other than integration. However, the higher order structure of IN that is required for its non-enzymatic functions remains to be delineated. This is the next major challenge in the field of IN structural biology hoping to be a platform for the development of novel IN inhibitors to treat human immunodeficiency virus type 1 infectious disease.
Highlights
Takao Masuda*The crystal structure of prototype foamy virus IN bound to cognate viral DNA (vDNA) ends, a complex referred to as the intasome, has recently been resolved
Reverse transcription of viral RNA into double-stranded DNA, and the subsequent insertion of the synthesized viral DNA into a host chromosome, are characteristic features of retroviruses including human immunodeficiency virus type 1 (HIV-1)
NON-ENZYMATIC FUNCTIONS OF IN Originally, we found that introduction of amino acid substitutions at conserved HHCC residues in the N-terminal domain (NTD) of HIV-1 IN resulted in almost complete abrogation of proviral DNA formation, concomitant with a severe reduction in vDNA synthesis
Summary
The crystal structure of prototype foamy virus IN bound to cognate vDNA ends, a complex referred to as the intasome, has recently been resolved. Structure analysis of the intasome revealed a tetramer structure of IN that was required for its catalytic function, and showed the inhibitory mechanism of the IN inhibitor. Genetic analysis of IN has revealed additional non-enzymatic roles during viral replication cycles at several steps other than integration. The higher order structure of IN that is required for its non-enzymatic functions remains to be delineated. This is the major challenge in the field of IN structural biology hoping to be a platform for the development of novel IN inhibitors to treat human immunodeficiency virus type 1 infectious disease
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