Ann Taylor/HIV Protease
From Proteopedia
FunctionHuman Immunodeficiency Virus (HIV) is the cause of Acquired Immunodeficiency Syndrome (AIDS). HIV synthesizes all of its proteins as one long chain. This long chain must be cut into individual component proteins. This hydrolysis reaction is catalyzed by HIV-1 protease. Since this isn't a process that is used for normal human proteins, it is a target for medications that treat HIV and AIDS. Structure of HIV-1 ProteaseThe X-ray crystallography structure of HIV-1 protease[1][2] reveals that it is composed of , each consisting of 99 amino acid residues. The subunits come together in such as way as to form a tunnel where they meet. This tunnel is of critical importance 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 tunnel appears to be too narrow to let it in. The key is the two flexible flaps on the top of the tunnel that move to allow proteins to enter the tunnel. The flaps undergo a dramatic movement, shifting from an open to a closed conformation to bind the target in an appropriate conformation for cleavage. The secondary structure of HIV protease is mostly beta strands in alternating directions to form a structure known as a beta jelly roll. In this color scheme, the N terminus for each protein chain is blue, and moves through the rainbow of colors (light blue, green, yellow, and orange) to the C terminus, shown in red. How HIV Protease worksHIV protease is categorized as an Aspartate Protease. This means that aspartic acid side chains are required for its function. In HIV protease, one aspartic acid from each protein chain interacts with the peptide chain to position it in a way that water can break the peptide bond. How drugs inhibit HIV ProteaseThe first protease inhibitor approved by the FDA for the treatment of HIV was . It inhibits HIV protease by binding tightly in the active site tunnel, preventing the binding of polyproteins. Its chemical structure mimics the tetrahedral intermediate of the hydrolytic reaction, thereby interacting strongly with the catalytic Asp residues.[3] 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 Leu 10 and Ile 50[4]. New generations of protease inhibitors such as and Viracept block HIV Protease in similar ways.
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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
