Immunodeficiency virus protease
From Proteopedia
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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 -- afterall, the tunnel does not seem so accessible. The key are 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. | 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 -- afterall, the tunnel does not seem so accessible. The key are 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. | ||
| - | Other drugs used to treat patients infected with the HIV virus include (PDB entry [[1hsg]]), Ritonavir (PDB entry [[1hxw]]), and Nelfinavir (PDB entry [[1ohr]]). | + | 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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Revision as of 11:32, 19 August 2008
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| 2nmz, resolution 0.97Å () | |||||||||
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| Ligands: | , | ||||||||
| Gene: | gag (Human immunodeficiency virus 1) | ||||||||
| Activity: | HIV-1 retropepsin, with EC number 3.4.23.16 | ||||||||
| Related: | 2nmw, 2nmy, 2nnk, 2nnp | ||||||||
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| Resources: | FirstGlance, OCA, RCSB, PDBsum | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
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, (PDB entry 2nmz).
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.
Looking at the structure of HIV-1 protease, we see that the protein is composed of , 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 , 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 of the protease: (residue numbers 25, 26, and 27 on one chain and 125, 126, and 127 on the second). 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.
Saquinavir was the the first protease inhibitor approved by the FDA for the treatment of HIV. It inhibits HIV-1 protease by , 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 -- afterall, the tunnel does not seem so accessible. The key are the two flexible flaps on the top of the tunnel that can (large scene, takes a while to load) to allow proteins to enter the tunnel. A 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.
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).
References
- 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:17243183
- 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:1799632
Links
- HIV-1 Protease featured in David S. Goodsell's Molecule of the Month
- HIV-1 Protease in Wikipedia
This page is not a fully developed page, but was created as an example for the press release of the Proteopedia article in the open-access journal Genome Biology. Please expand this page with additional information and references.
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