Objective: To define the extent of amino acid protease (PR) conservation in vivo in the absence and presence of pharmacological pressure in a large patient cohort. Methods: Plasma-derived complete protein PR sequences from a well-defined cohort of 1096 HIV-1 infected individuals (457 drug-naive and 639 under antiretroviral therapy including PR-inhibitors) were obtained and analysed, and are discussed in a structural context. Results: In naive patients, the PR sequence showed conservation (< 1% variability) in 68 out of 99 (69%) residues. Five large conserved regions were observed, one (P1-P9) at the N-terminal site, another (E21-V32) comprised the catalytic active-site, a third (P44-V56) contained the flap, a fourth contained the region G78-N88, and another (G94-F99) contained the C-terminal site. In PR-inhibitor treated patients, the appearance of mutations primarily associated with drug resistance determined a decrease of amino acid invariance to 45 out of 99 residues (45% conservation). The overall degree of enzyme conservation, when compared to the PR sequences in drug-naive patients, was preserved at the N- and C-terminal regions, whereas the other large conserved areas decreased to smaller domains containing, respectively, the active-site residues D25-D29, the tip of the flap G49-G52, and the G78-P81 and G86-R87 turns. Conclusions: Amino acid conservation in HIV PR can be minimally present in 45 residues out of 99. Identification of these invariable residues, with crucial roles in dimer stability, protein flexibility and catalytic activity, and their mapping on the three-dimensional structure of the enzyme will help guide the design of novel resistance-evading drugs. © 2004 Lippincott Williams & Wilkins.

CECCHERINI SILBERSTEIN, F., Erba, F., Gago, F., Bertoli, A., Forbici, F., Bellocchi, M., et al. (2004). Identification of the minimal conserved structure of HIV-1 protease in the presence and absence of drug pressure. AIDS, 18(12), 11-19 [10.1097/01.aids.0000131394.76221.02].

Identification of the minimal conserved structure of HIV-1 protease in the presence and absence of drug pressure

CECCHERINI SILBERSTEIN, FRANCESCA;ERBA, FULVIO;BERTOLI, ADA;PERNO, CARLO FEDERICO
2004-01-01

Abstract

Objective: To define the extent of amino acid protease (PR) conservation in vivo in the absence and presence of pharmacological pressure in a large patient cohort. Methods: Plasma-derived complete protein PR sequences from a well-defined cohort of 1096 HIV-1 infected individuals (457 drug-naive and 639 under antiretroviral therapy including PR-inhibitors) were obtained and analysed, and are discussed in a structural context. Results: In naive patients, the PR sequence showed conservation (< 1% variability) in 68 out of 99 (69%) residues. Five large conserved regions were observed, one (P1-P9) at the N-terminal site, another (E21-V32) comprised the catalytic active-site, a third (P44-V56) contained the flap, a fourth contained the region G78-N88, and another (G94-F99) contained the C-terminal site. In PR-inhibitor treated patients, the appearance of mutations primarily associated with drug resistance determined a decrease of amino acid invariance to 45 out of 99 residues (45% conservation). The overall degree of enzyme conservation, when compared to the PR sequences in drug-naive patients, was preserved at the N- and C-terminal regions, whereas the other large conserved areas decreased to smaller domains containing, respectively, the active-site residues D25-D29, the tip of the flap G49-G52, and the G78-P81 and G86-R87 turns. Conclusions: Amino acid conservation in HIV PR can be minimally present in 45 residues out of 99. Identification of these invariable residues, with crucial roles in dimer stability, protein flexibility and catalytic activity, and their mapping on the three-dimensional structure of the enzyme will help guide the design of novel resistance-evading drugs. © 2004 Lippincott Williams & Wilkins.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/10
English
amprenavir; dimer; indinavir; lopinavir; nelfinavir; proteinase; proteinase inhibitor; ritonavir; saquinavir; amino acid sequence; amino terminal sequence; antibiotic resistance; article; blood analysis; carboxy terminal sequence; catalysis; cohort analysis; comparative study; controlled study; enzyme active site; enzyme structure; genetic conservation; genetic variability; highly active antiretroviral therapy; human; Human immunodeficiency virus 1; Human immunodeficiency virus infection; major clinical study; nucleotide sequence; priority journal; protein analysis; protein domain; protein variant; viral genetics; virus mutation; Amino Acid Sequence; Antiretroviral Therapy, Highly Active; Cohort Studies; Conserved Sequence; Drug Resistance, Viral; Genotype; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Models, Chemical; Models, Genetic; Mutation; Polymorphism, Genetic
CECCHERINI SILBERSTEIN, F., Erba, F., Gago, F., Bertoli, A., Forbici, F., Bellocchi, M., et al. (2004). Identification of the minimal conserved structure of HIV-1 protease in the presence and absence of drug pressure. AIDS, 18(12), 11-19 [10.1097/01.aids.0000131394.76221.02].
CECCHERINI SILBERSTEIN, F; Erba, F; Gago, F; Bertoli, A; Forbici, F; Bellocchi, M; Gori, C; D'Arrigo, R; Marcon, L; Balotta, C; Antinori, A; Monforte, A; Perno, Cf
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/34520
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