Ann Taylor/HIV Protease

The X-ray crystallography structure of HIV-1 protease<ref>PMID:2548279</ref><ref>PMID:2682266</ref> reveals that it is composed of <scene name='User:David_Canner/Sandbox_HIV/Identical_subunits/1'>two subunits</scene>, each consisting of 99 amino acid residues. The subunits come together in such as way as to form a <scene name='User:David_Canner/Sandbox_HIV/Tunnel/1'>tunnel</scene> where they meet. This tunnel is important because this is where the long protein chain substrate binds to HIV protease. You may be wondering how a polyprotein makes its way into the tunnel, as the<scene name='User:David_Canner/Sandbox_HIV/Narrow_tunnel/1'> tunnel appears to be too narrow </scene> to let it in. The key is the two flexible flaps on the top of the tunnel that <scene name='User:David_Canner/Sandbox_HIV/Hiv_tunnel_morph/3'>move to allow proteins</scene> to enter the tunnel. The flaps <scene name='User:David_Canner/Sandbox_HIV/Hiv_tunnel_morph_flaps/2'>undergo a dramatic movement</scene>, shifting from an open to a closed conformation to bind the target in an appropriate conformation for cleavage.

==How HIV Protease works==

HIV protease is categorized as an Aspartate Protease. This means that <scene name='User:David_Canner/Sandbox_HIV/Catalytic_asp/1'>aspartic acid side chains</scene> are required for its function. In HIV protease, one aspartic acid from each protein chain interact with the <scene name='31/315240/Saquinavir_cat_water/2'>water</scene> that cleaves the peptide bond.

==How drugs inhibit HIV Protease==

<scene name='User:David_Canner/Sandbox_HIV/Saquinavir/4'>Saquinavir</scene> ([[Invirase]]) was the first protease inhibitor approved by the FDA for the treatment of HIV. It inhibits HIV protease by <scene name='User:David_Canner/Sandbox_HIV/Saquinavir_tunnel/1'>binding tightly in the active site tunnel</scene>, preventing the binding of polyproteins. Its chemical structure mimics the tetrahedral intermediate of the hydrolytic reaction, thereby <scene name='User:David_Canner/Sandbox_HIV/Saquinavir_cat/3'>interacting strongly with the catalytic Asp residues</scene>.<ref>PMID:17243183</ref> Saquinavir is essentially an uncleavable ligand, as indicated by the <scene name='User:David_Canner/Sandbox_HIV/Hiv_morph2/9'> similar conformational changes in the protease flaps </scene> on binding saquinavir or a polypeptide. Resistance to saquinavir is due to alterations in the HIV protease sequence, including the mutation of <scene name='31/315240/Saquinavir_mut/1'>Leu 10 and Ile 50</scene><ref>PMID: 8969180</ref>. Drugs used to treat HIV infection that inhibit <scene name='User:David_Canner/Sandbox_HIV/Inhibitor_intro/1'>HIV protease</scene> include <scene name='User:David_Canner/Sandbox_HIV/Indinavir/2'>Indinavir </scene> ([[Crixivan]]), <scene name='User:David_Canner/Sandbox_HIV/Ritonavir/1'>Ritonavir</scene> ([[Norvir]]), [[Saquinavir]], [[Tipranavir]], [[Amprenavir]] (Agenerase), [[Atazanavir]] (Rayataz), [[Darunavir]] (Prezista), [[Fosamprenavir]] (Lexiva or Telzir), [[Lopinavir]] (Kaletra), [[Nelfinavir]] (Viracept) and <scene name='User:David_Canner/Sandbox_HIV/Nelfinavir/2'>Nelfinavir</scene> ([[Viracept]]).