2p3d
From Proteopedia
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'''Crystal Structure of the multi-drug resistant mutant subtype F HIV protease complexed with TL-3 inhibitor''' | '''Crystal Structure of the multi-drug resistant mutant subtype F HIV protease complexed with TL-3 inhibitor''' | ||
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==About this Structure== | ==About this Structure== | ||
| - | + | Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2P3D OCA]. | |
==Reference== | ==Reference== | ||
Structural characterization of B and non-B subtypes of HIV-protease: insights into the natural susceptibility to drug resistance development., Sanches M, Krauchenco S, Martins NH, Gustchina A, Wlodawer A, Polikarpov I, J Mol Biol. 2007 Jun 15;369(4):1029-40. Epub 2007 Mar 24. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17467738 17467738] | Structural characterization of B and non-B subtypes of HIV-protease: insights into the natural susceptibility to drug resistance development., Sanches M, Krauchenco S, Martins NH, Gustchina A, Wlodawer A, Polikarpov I, J Mol Biol. 2007 Jun 15;369(4):1029-40. Epub 2007 Mar 24. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17467738 17467738] | ||
[[Category: HIV-1 retropepsin]] | [[Category: HIV-1 retropepsin]] | ||
| - | [[Category: Human immunodeficiency virus 1]] | ||
| - | [[Category: Protein complex]] | ||
[[Category: Gustchina, A.]] | [[Category: Gustchina, A.]] | ||
[[Category: Krauchenco, S.]] | [[Category: Krauchenco, S.]] | ||
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[[Category: Sanches, M.]] | [[Category: Sanches, M.]] | ||
[[Category: Wlodawer, A.]] | [[Category: Wlodawer, A.]] | ||
| - | [[Category: | + | [[Category: Multi-drug resistant mutant subtype f hiv protease]] |
| - | [[Category: | + | [[Category: Non-b hiv protease]] |
| - | [[Category: | + | [[Category: Protease-inhibitor complex]] |
| - | [[Category: | + | [[Category: Tl-3 inhibitor]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 12:15:37 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 09:15, 4 May 2008
Crystal Structure of the multi-drug resistant mutant subtype F HIV protease complexed with TL-3 inhibitor
Overview
Although a majority of HIV-1 infections in Brazil are caused by the subtype B virus (also prevalent in the United States and Western Europe), viral subtypes F and C are also found very frequently. Genomic differences between the subtypes give rise to sequence variations in the encoded proteins, including the HIV-1 protease. The current anti-HIV drugs have been developed primarily against subtype B and the effects arising from the combination of drug-resistance mutations with the naturally existing polymorphisms in non-B HIV-1 subtypes are only beginning to be elucidated. To gain more insights into the structure and function of different variants of HIV proteases, we have determined a 2.1 A structure of the native subtype F HIV-1 protease (PR) in complex with the protease inhibitor TL-3. We have also solved crystal structures of two multi-drug resistant mutant HIV PRs in complex with TL-3, from subtype B (Bmut) carrying the primary mutations V82A and L90M, and from subtype F (Fmut) carrying the primary mutation V82A plus the secondary mutation M36I, at 1.75 A and 2.8 A resolution, respectively. The proteases Bmut, Fwt and Fmut exhibit sevenfold, threefold, and 54-fold resistance to TL-3, respectively. In addition, the structure of subtype B wild type HIV-PR in complex with TL-3 has been redetermined in space group P6(1), consistent with the other three structures. Our results show that the primary mutation V82A causes the known effect of collapsing the S1/S1' pockets that ultimately lead to the reduced inhibitory effect of TL-3. Our results further indicate that two naturally occurring polymorphic substitutions in subtype F and other non-B HIV proteases, M36I and L89M, may lead to early development of drug resistance in patients infected with non-B HIV subtypes.
About this Structure
Full crystallographic information is available from OCA.
Reference
Structural characterization of B and non-B subtypes of HIV-protease: insights into the natural susceptibility to drug resistance development., Sanches M, Krauchenco S, Martins NH, Gustchina A, Wlodawer A, Polikarpov I, J Mol Biol. 2007 Jun 15;369(4):1029-40. Epub 2007 Mar 24. PMID:17467738 Page seeded by OCA on Sun May 4 12:15:37 2008
