Ann Taylor/HIV Protease
From Proteopedia
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==Structure of HIV-1 Protease== | ==Structure of HIV-1 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 | + | 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. |
The <scene name='90/909295/Secondary_structure/1'>secondary structure</scene> of HIV protease is mostly beta strands in alternating directions to form a structure known as a <scene name='90/909295/Rainbow/1'>beta jelly roll</scene>. In this color scheme, the N terminus for each protein chain is <b><span class="text-blue">blue</span></b>, and moves through the rainbow of colors (light blue, green, yellow, and orange) to the C terminus, shown in <b><span class="text-red">red</span></b>. | The <scene name='90/909295/Secondary_structure/1'>secondary structure</scene> of HIV protease is mostly beta strands in alternating directions to form a structure known as a <scene name='90/909295/Rainbow/1'>beta jelly roll</scene>. In this color scheme, the N terminus for each protein chain is <b><span class="text-blue">blue</span></b>, and moves through the rainbow of colors (light blue, green, yellow, and orange) to the C terminus, shown in <b><span class="text-red">red</span></b>. | ||
| + | ==How HIV Protease works== | ||
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| + | 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== | ||
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| + | <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]]). | ||
</StructureSection> | </StructureSection> | ||
== References == | == References == | ||
<references/> | <references/> | ||
Revision as of 16:27, 7 April 2022
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References
- ↑ Wlodawer A, Miller M, Jaskolski M, Sathyanarayana BK, Baldwin E, Weber IT, Selk LM, Clawson L, Schneider J, Kent SB. Conserved folding in retroviral proteases: crystal structure of a synthetic HIV-1 protease. Science. 1989 Aug 11;245(4918):616-21. PMID:2548279
- ↑ Lapatto R, Blundell T, Hemmings A, Overington J, Wilderspin A, Wood S, Merson JR, Whittle PJ, Danley DE, Geoghegan KF, et al.. X-ray analysis of HIV-1 proteinase at 2.7 A resolution confirms structural homology among retroviral enzymes. Nature. 1989 Nov 16;342(6247):299-302. PMID:2682266 doi:http://dx.doi.org/10.1038/342299a0
- ↑ Tie Y, Kovalevsky AY, Boross P, Wang YF, Ghosh AK, Tozser J, Harrison RW, Weber IT. Atomic resolution crystal structures of HIV-1 protease and mutants V82A and I84V with saquinavir. Proteins. 2007 Apr 1;67(1):232-42. PMID:17243183 doi:10.1002/prot.21304
- ↑ Maschera B, Darby G, Palu G, Wright LL, Tisdale M, Myers R, Blair ED, Furfine ES. Human immunodeficiency virus. Mutations in the viral protease that confer resistance to saquinavir increase the dissociation rate constant of the protease-saquinavir complex. J Biol Chem. 1996 Dec 27;271(52):33231-5. PMID:8969180
