Immunodeficiency virus protease
From Proteopedia
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==Structure of HIV-1 Protease== | ==Structure of HIV-1 Protease== | ||
| - | The X-ray structure of HIV-1 protease<ref>PMID:2548279</ref> 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> either interact with the incoming water OR protonate the carbonyl to make the carbon more electrophilic for the incoming <scene name='31/315240/Saquinavir_cat_water/2'>water</scene>. 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. | + | The X-ray structure of HIV-1 protease<ref>PMID:2548279</ref><ref>PMID:2682266</ref> 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> either interact with the incoming water OR protonate the carbonyl to make the carbon more electrophilic for the incoming <scene name='31/315240/Saquinavir_cat_water/2'>water</scene>. 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== | ||
Revision as of 14:10, 27 March 2016
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Additional Resources
For additional information, see:
- Human Immunodeficiency Virus
- Structural Biology of HIV, an interactive Flash graphic of the virion with explanations of its components.
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
- ↑ Naicker P, Achilonu I, Fanucchi S, Fernandes M, Ibrahim MA, Dirr HW, Soliman ME, Sayed Y. Structural insights into the South African HIV-1 subtype C protease: impact of hinge region dynamics and flap flexibility in drug resistance. J Biomol Struct Dyn. 2012 Nov 12. PMID:23140382 doi:10.1080/07391102.2012.736774
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