Immunodeficiency virus protease

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{{STRUCTURE_2nmz| PDB=2nmz | SCENE= HIV-1_protease/2nmz/3 }}
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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'>
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HIV is a notoriously lethal virus that is known to cause AIDS. There currently is no cure or vaccine. But, scientists 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]], seen here on the right in complex with a potent drug used for slowing the progression of HIV, <scene name='HIV-1_protease/2nmz_saquinavir/2'>Saquinavir</scene> (PDB entry [[2nmz]]).
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[[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.
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HIV-1 protease is a 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, or cut, 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.
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===Structure of HIV-1 Protease===
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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/2'> two Asp-Thr-Gly catalytic triads</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.
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Looking at the structure of HIV-1 protease, we see that the protein is composed of <scene name='HIV-1_protease/2nmz_symmetric/2'>two symmetrically related subunits</scene>, shown here in [[cartoon backbone representation]] to highlight [[secondary structure]]. Each subunit consists of the same small chain of only 99 amino acids. The subunits come together in such as way as to <scene name='HIV-1_protease/2nmz_tunnel/1'>form a tunnel where they meet</scene>, shown here in [[spacefilling representation]] to showcase the physical surface of the protein. The protein to be cleaved sits in this tunnel. In the middle of the tunnel is the <scene name='HIV-1_protease/2nmz_triads/1'>active site</scene> of the protease: <scene name='HIV-1_protease/2nmz_triadslabeled/2'>two Asp-Thr-Gly catalytic triads</scene> (residue numbers 25, 26, and 27 on one chain and 125, 126, and 127 on the second). <scene name='HIV-1_protease/2nmz_aspslabeled/1'>The two Asp's</scene> act as the main catalytic residues in the active site and use a water molecule to help break the protein chain that binds in the tunnel.
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===Medical Implications===
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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/1'>interacting strongly with the catalytic triad</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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Saquinavir was the the first protease inhibitor approved by the FDA for the treatment of HIV. It inhibits HIV-1 protease by <scene name='HIV-1_protease/2nmz_saquinavir_spacefill/1'>binding tightly to the active site tunnel</scene>, thus preventing the protease from cleaving any protein chains. You may be wondering how a protein to be cleaved makes its way into the active-site tunnel to begin with -- after all, the tunnel does not seem so accessible. The key is the two flexible flaps on the top of the tunnel that can <scene name='HIV-1_protease/Hiv1_protease_morph/4'>move</scene> (large scene, takes a while to load) to allow proteins to enter the tunnel. A <scene name='HIV-1_protease/Hiv1_p_morph_sp/2'>spacefill view of the flexible flaps</scene> is also illuminating, as the change in the accessibility of the tunnel becomes more obvious. This movement of the flexible flaps is simulated by morphing between two crystal structures, the first being the native HIV-1 protease structure with no inhibitor bound (PDB entry [[1hhp]]) and the second being the HIV-1 protease complexed with Saquinavir.
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__NOTOC__
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Other drugs used to treat patients infected with the HIV virus include Indinavir (PDB entry [[1hsg]]), Ritonavir (PDB entry [[1hxw]]), and Nelfinavir (PDB entry [[1ohr]]).
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</StructureSection>
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{{Clear}}
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==Additional Resources==
==Additional Resources==
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==References==
==References==
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*Atomic resolution crystal structures of HIV-1 protease and mutants V82A and I84V with saquinavir., Tie Y, Kovalevsky AY, Boross P, Wang YF, Ghosh AK, Tozser J, Harrison RW, Weber IT, Proteins. 2007 Apr 1;67(1):232-42. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17243183 17243183]
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<references/>
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*The three-dimensional structure of the aspartyl protease from the HIV-1 isolate BRU., Spinelli S, Liu QZ, Alzari PM, Hirel PH, Poljak RJ, Biochimie. 1991 Nov;73(11):1391-6. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/1799632 1799632]
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==Links==
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* HIV-1 Protease featured in [[User:David S. Goodsell | David S. Goodsell's]] [http://mgl.scripps.edu/people/goodsell/pdb/pdb6/pdb6_1.html Molecule of the Month]
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* HIV-1 Protease in [http://en.wikipedia.org/wiki/HIV-1_protease Wikipedia]
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Revision as of 08:06, 1 December 2010

Structure of HIV Protease

Drag the structure with the mouse to rotate

Additional Resources

For additional information, see: Human Immunodeficiency Virus

References

  1. ↑ 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
  2. ↑ 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
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