HIV-1 Integrase is a 3 domain protein; each domain has a different function that when combined with the other 2 domains catalyzes the transefer of HIV-1 DNA into the host's genome. Domain 1 consists of 3 alpha-helices and a zinc binding site which trims off the 3' ends of viral DNA prior to integration into the host DNA. It is suspected that this removes any non-templated (non-paired) DNA that reverse transcriptase (RT) may have added during RNA to DNA replication. Domain 2 (shown at right) is the domain responsible for the transfer of viral DNAinto the host DNA. Consisting of 6 alpha-helices and 4 beta-strands this domain is able to integrate as well as disintegrate (remove) viral DNA from host DNA. Domain 3 contains a 5
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stranded beta-barrel resembling the SH3 domain, which is responsible for binding and holding DNA, so that Domain 2 can transfer viral DNA into the host DNA. Although Domains 1 and 3 are important for the proper functioning of the protein as a whole, they are not essential in the function of Domain 2. Since only Domain 2 exhibits transferase activity it will be the focus. The active site of Domain 2 is suspected to involve Asp 64, Asp 116, and Asp 152. These residues are known to bind either Magnesium or Manganese metal ions. In either case the bound metal ion is located in the active site and stabilizes the DNA while it is being transfered into or out of the host genome. Unfortunately the only way known to crystallize HIV-1 integrase prohibits it from binding metal ions. This has to do with the protein binding cacodylate (CAC) in the solvent. A stuctural change occurs around the area of beta-strand 4, which is where Asp 64 is located, when CAC binds to the protein. The loop containing Asp 116, located in the region around beta-strand 4, moves relative to the metal ion and pulls the beta-strand containing Asp 64 along when CAC binds making it unable to bind the metal ion(s) that are present. Without Asp 152 binding the metal ion Asp 64 and Asp 116 are not able to hold the ion in place long enough for the reaction to be catalyzed so the enzyme becomes inactivated.
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