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<StructureSection load='2nmz' size='500' side='right' background='none' scene='User:David_Canner/Sandbox_HIV/Opening/2' caption='Structure of HIV Protease'>
<StructureSection load='2nmz' size='500' side='right' background='none' scene='User:David_Canner/Sandbox_HIV/Opening/2' caption='Structure of HIV Protease'>
[[Image:CannergreyHIV2.png|220px|left]][[Human Immunodeficiency Virus]] is a notoriously lethal virus that is known to cause AIDS. It is a homodimeric protein made by the HIV virus that is crucial to the virus's infectious capacity. The virus makes certain proteins that need to be cleaved, in order to transform into mature, fully-functional proteins that can allow the virus to infect new cells. HIV-1 protease is responsible for cleaving these nascent proteins into their mature form.
=HIV-Protease=
[[Image:CannergreyHIV2.png|220px|left]][[Human Immunodeficiency Virus]] (HIV) is the cause of Acquired Immunodeficiency Syndrome (AIDS). HIV directs the synthesis of several polyproteins, which each consist of several tandemly linked proteins. The maturation of the virus to its infectious form requires that these polyproteins be cleaved to their component proteins. <scene name='User:David_Canner/Sandbox_HIV/Opening/2'>HIV-1 protease</scene>, a homodimeric enzyme, is responsible for doing so and is therefore crucial to the virus's infectious capacity.
===Structure of HIV-1 Protease===
===Structure of HIV-1 Protease===
Looking at the structure of HIV-1 protease, we see that the protein is composed of <scene name='User:David_Canner/Sandbox_HIV/Identical_subunits/1'>two symmetrically related subunits</scene>, each consisting of identical 99 amino acid chains. The subunits come together in such as way as to <scene name='User:David_Canner/Sandbox_HIV/Tunnel/1'>form a tunnel where they meet</scene>. This tunnel is of critical importance as it is the location where nascent proteins are bound before cleavage. In the middle of the tunnel is the active site of the protease:<scene name='User:David_Canner/Sandbox_HIV/Catalytic_triad/2'> two Asp-Thr-Gly catalytic triads</scene>. The two Asp's act as <scene name='User:David_Canner/Sandbox_HIV/Catalytic_asp/1'>the main catalytic residues</scene> in the active site and use a water molecule to help break the protein chain that binds in the tunnel. <ref>PMID:1799632</ref> You may be wondering how a protein to be cleaved makes its way into the active-site tunnel, as the<scene name='User:David_Canner/Sandbox_HIV/Narrow_tunnel/1'> tunnel appears to be rather narrow</scene>. The key is the two flexible flaps on the top of the tunnel that can <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 closed conformation to securly binding its target in an appropriate conformation for cleavage.
The X-ray structure of HIV-1 protease reveals that it is composed of <scene name='User:David_Canner/Sandbox_HIV/Identical_subunits/1'>two symmetrically related subunits</scene>, each consisting of 99 amino acid residues. The subunits come together in such as way as to <scene name='User:David_Canner/Sandbox_HIV/Tunnel/1'>form a tunnel where they meet</scene>. This tunnel is of critical importance because the active site of the protease is located in its interior. The active site consists of <scene name='User:David_Canner/Sandbox_HIV/Catalytic_triad/3'> two Asp-Thr-Gly conserved sequences</scene>, making it a member of the aspartyl protease family. The two Asp's are <scene name='User:David_Canner/Sandbox_HIV/Catalytic_asp/1'>essential catalytic residues</scene> that activate a water molecule to hydrolytically cleave the polyprotein that binds in the tunnel.<ref>PMID:1799632</ref> You may be wondering how a polyprotein makes its way into the active-site tunnel, as the<scene name='User:David_Canner/Sandbox_HIV/Narrow_tunnel/1'> tunnel appears to be too narrow </scene> to admit it. 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.
===Medical Implications===
===Medical Implications===
There currently is no cure or vaccine against contracting HIV. AIDS researchers, however, have discovered treatments that can slow progression of the HIV virus, thanks in large part to our understanding of the structure of HIV-1 protease. <scene name='User:David_Canner/Sandbox_HIV/Saquinavir/4'>Saquinavir</scene> was the the first protease inhibitor approved by the FDA for the treatment of HIV. It inhibits HIV-1 protease by <scene name='User:David_Canner/Sandbox_HIV/Saquinavir_tunnel/1'>binding tightly to the active site tunnel</scene>, preventing nascent peptides from entering and <scene name='User:David_Canner/Sandbox_HIV/Saquinavir_cat/1'>interfering with the catalytic triad</scene>.<ref>PMID:17243183</ref> Saquinavir effectively acts like an uncleavable ligand, highlighted by the protease flaps undergoing <scene name='User:David_Canner/Sandbox_HIV/Hiv_morph2/9'>a similar movement</scene> upon binding. Other drugs used to treat patients infected with the HIV virus which inhibit <scene name='User:David_Canner/Sandbox_HIV/Inhibitor_intro/1'>HIV-1 Protease</scene> include <scene name='User:David_Canner/Sandbox_HIV/Indinavir/2'>Indinavir </scene> ([[1hsg]]), <scene name='User:David_Canner/Sandbox_HIV/Ritonavir/1'>Ritonavir</scene> ([[1hxw]]), and <scene name='User:David_Canner/Sandbox_HIV/Nelfinavir/2'>Nelfinavir</scene> ([[1ohr]]).
There currently is no cure or vaccine against HIV. Researchers, however, have discovered treatments that can halt and even reverse the progression of AIDS, due in large part to our understanding of the structure of HIV-1 protease. <scene name='User:David_Canner/Sandbox_HIV/Saquinavir/4'>Saquinavir</scene> 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 . Other 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> ([[1hsg]]), <scene name='User:David_Canner/Sandbox_HIV/Ritonavir/1'>Ritonavir</scene> ([[1hxw]]), and <scene name='User:David_Canner/Sandbox_HIV/Nelfinavir/2'>Nelfinavir</scene> ([[1ohr]]).
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Latest revision as of 09:33, 2 December 2010
HIV-Protease
Human Immunodeficiency Virus (HIV) is the cause of Acquired Immunodeficiency Syndrome (AIDS). HIV directs the synthesis of several polyproteins, which each consist of several tandemly linked proteins. The maturation of the virus to its infectious form requires that these polyproteins be cleaved to their component proteins. , a homodimeric enzyme, is responsible for doing so and is therefore crucial to the virus's infectious capacity.
Structure of HIV-1 Protease
The X-ray structure of HIV-1 protease reveals that it is composed of , each consisting of 99 amino acid residues. The subunits come together in such as way as to . This tunnel is of critical importance because the active site of the protease is located in its interior. The active site consists of , making it a member of the aspartyl protease family. The two Asp's are that activate a water molecule to hydrolytically cleave the polyprotein that binds in the tunnel.[1] You may be wondering how a polyprotein makes its way into the active-site tunnel, as the to admit it. The key is the two flexible flaps on the top of the tunnel that to enter the tunnel. The flaps , shifting from an open to a closed conformation to bind the target in an appropriate conformation for cleavage.
Medical Implications
There currently is no cure or vaccine against HIV. Researchers, however, have discovered treatments that can halt and even reverse the progression of AIDS, due in large part to our understanding of the structure of HIV-1 protease. was the first protease inhibitor approved by the FDA for the treatment of HIV. It inhibits HIV protease by , preventing the binding of polyproteins. Its chemical structure mimics the tetrahedral intermediate of the hydrolytic reaction, thereby .[2] Saquinavir is essentially an uncleavable ligand, as indicated by the on binding saquinavir or a polypeptide . Other drugs used to treat HIV infection that inhibit include (1hsg), (1hxw), and (1ohr).
↑Spinelli S, Liu QZ, Alzari PM, Hirel PH, Poljak RJ. The three-dimensional structure of the aspartyl protease from the HIV-1 isolate BRU. Biochimie. 1991 Nov;73(11):1391-6. PMID:1799632
↑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
