Ann Taylor/HIV Protease
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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 interacts with the <scene name='31/315240/Saquinavir_cat_water/2'>peptide chain</scene> to position it in a way that water can break the peptide bond. | 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 interacts with the <scene name='31/315240/Saquinavir_cat_water/2'>peptide chain</scene> to position it in a way that water can break the peptide bond. | ||
+ | ==How drugs inhibit HIV Protease== | ||
+ | The first protease inhibitor approved by the FDA for the treatment of HIV was <scene name='User:David_Canner/Sandbox_HIV/Saquinavir/4'>Saquinavir</scene> 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> Since Saquinavir doesn't have a bond that can be broken by water, it gets "stuck" in the active site, and prevents the actual HIV protein from being able to bind to the enzyme. Unfortunately, variations in the sequences of HIV protease provide resistance to saquinaivr, including the mutation of <scene name='31/315240/Saquinavir_mut/1'>Leu 10 and Ile 50</scene><ref>PMID: 8969180</ref>. | ||
</StructureSection> | </StructureSection> | ||
== References == | == References == | ||
<references/> | <references/> |
Revision as of 16:44, 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