IFIS - LITORAL   24734
INSTITUTO DE FISICA DEL LITORAL
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Structural and functional relationship of a key Lys residue in human elomerase reverse transcriptase and HIV-1 RT proteins: a comparative study
Autor/es:
F.E. HERRERA; SJ. SFERCO
Lugar:
Carlos Paz, Provincia de Córdoba
Reunión:
Congreso; SAB2013; 2013
Institución organizadora:
Sociedad Argentina de Biofísica
Resumen:
Reverse Transcriptase (RT) proteins add dNTP to an existing DNA primer having RNA as a template.  HIV-1 and telomerase reverse transcriptase (TERT) proteins are well known examples. Both have a RT sequence domain, formed by several motifs (1, 2, A ,B?, C, D and E) identified from a few conserved key residues. Among them, three conserved Asp residues (from motifs A and C) are essential for the catalytic polymerase activity, both in HIV-1 as well as in telomerases. On the other hand, mutations of the other key residues modify some properties but do not quench the catalytic activity to zero. The exception is the Lys902 (located in motif D) of human TERT: when mutated to Ala, Gln or Asn, a null catalytic activity is measured in vitro. While, when the corresponding Lys220 in HIV-1 is mutated to Gln, the catalytic activity is still significant compared to WT. In this work, a comparative study was done in order to understand why the mutations of the conserved Lys in motif D, are crucial in hTERT, but not in HIV-1. A good validated theoretical model for the human TERT was obtained (the experimental structure is not known) and 10 ns of molecular dynamics simulations at 300K for the WT, and each of the three mutations were performed. Similarly, the same kind of MD simulations for the WT and mutated HIV-1, from an experimental structure were also performed. The results suggest that the Lys902 participates directly into the catalytic site of human TERT and therefore no mutations are tolerated. On the other side, the corresponding Lys in motif D of HIV-1 is found far away from the catalytic site, suggesting also that an exchange of roles with the neighbor Lys219 might occur.
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