Structural characterization of B and non-B subtypes of HIV-protease: insigths into the natural susceptibility to drug resistance development
| Autor: | Alla Gustchina, Alexander Wlodawer, Mário Antônio Sanches, Igor Polikarpov, Sandra Krauchenco, Nadia H. Martins |
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| Rok vydání: | 2007 |
| Předmět: |
Models
Molecular Proteases medicine.medical_treatment Mutant Molecular Sequence Data Biology medicine.disease_cause Crystallography X-Ray Virus HIV Protease Structural Biology Drug Resistance Viral medicine Humans Protease inhibitor (pharmacology) Amino Acid Sequence Molecular Biology Subtypes of HIV Genetics Mutation CRISTALOGRAFIA FÍSICA Protease Polymorphism Genetic Wild type HIV Protease Inhibitors Virology Isoenzymes Sequence Alignment |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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