Computational studies of the interaction between the HIV-1 integrase tetramer and the cofactor LEDGF/p75: Insights from molecular dynamics simulations and the informational spectrum method
Апстракт
A crystal structure of the integrase binding domain (IBD) of the lens epithelium-derived growth factor (LEDGF/p75) in complex with the dimer of the HIV-1 integrase (IN) catalytic core domain (CCD) provides useful information that might help in the understanding of essential protein-protein contacts in HIV-1. However, mutagenic studies indicated that interactions between the full-length proteins were more extensive than the contacts observed in the co-crystal structure of the isolated domains. On the other hand, the biochemical characterization of the interaction between full-length IN and LEDGF/p75 has recently proved that LEDGF/p75 promotes IN tetramerization with two LEDGF/p75 IBD molecules bound to the IN tetramer. This experimental evidence suggests that to obtain a complete structural description of the interactions between the two proteins, the full-length tetrameric structure of IN should be considered. Our aim was to obtain a detailed picture of HIV-1 IN interactions with cellu...lar co-factors that was of general interest, particularly for the development of small molecule IN inhibitors, which mimic the IBD of LEDGF/p75. To this end, we performed bioinformatics analyses to identify protein sequence domains involved in long-range recognition. Subsequently, we applied molecular dynamics techniques to investigate the detailed interactions between the complete tetrameric form of IN and two molecules of the IBD of LEDGF/p75. Our dynamic picture is in agreement with experimental data and, thereby, provides new details of the IN-LEDGF/p75 interaction.
Кључне речи:
hot spots / IN Oligomerization / IN tetramer / protein-protein interactionsИзвор:
Proteins: Structure Function and Bioinformatics, 2010, 78, 16, 3396-3408Финансирање / пројекти:
- CHAARM - Combined Highly Active Anti-retroviral Microbicides (EU-FP7-242135)
- Ministero dellIstruzione, dellUniversita e della Ricerca [2008CE75SA_004], MSTD Republic of Serbia [143001]
DOI: 10.1002/prot.22847
ISSN: 0887-3585
PubMed: 20878714
WoS: 000284046400014
Scopus: 2-s2.0-78349299377
Колекције
Институција/група
VinčaTY - JOUR AU - Tintori, Cristina AU - Veljković, Nevena V. AU - Veljković, Veljko AU - Botta, Maurizio PY - 2010 UR - https://vinar.vin.bg.ac.rs/handle/123456789/4144 AB - A crystal structure of the integrase binding domain (IBD) of the lens epithelium-derived growth factor (LEDGF/p75) in complex with the dimer of the HIV-1 integrase (IN) catalytic core domain (CCD) provides useful information that might help in the understanding of essential protein-protein contacts in HIV-1. However, mutagenic studies indicated that interactions between the full-length proteins were more extensive than the contacts observed in the co-crystal structure of the isolated domains. On the other hand, the biochemical characterization of the interaction between full-length IN and LEDGF/p75 has recently proved that LEDGF/p75 promotes IN tetramerization with two LEDGF/p75 IBD molecules bound to the IN tetramer. This experimental evidence suggests that to obtain a complete structural description of the interactions between the two proteins, the full-length tetrameric structure of IN should be considered. Our aim was to obtain a detailed picture of HIV-1 IN interactions with cellular co-factors that was of general interest, particularly for the development of small molecule IN inhibitors, which mimic the IBD of LEDGF/p75. To this end, we performed bioinformatics analyses to identify protein sequence domains involved in long-range recognition. Subsequently, we applied molecular dynamics techniques to investigate the detailed interactions between the complete tetrameric form of IN and two molecules of the IBD of LEDGF/p75. Our dynamic picture is in agreement with experimental data and, thereby, provides new details of the IN-LEDGF/p75 interaction. T2 - Proteins: Structure Function and Bioinformatics T1 - Computational studies of the interaction between the HIV-1 integrase tetramer and the cofactor LEDGF/p75: Insights from molecular dynamics simulations and the informational spectrum method VL - 78 IS - 16 SP - 3396 EP - 3408 DO - 10.1002/prot.22847 ER -
@article{ author = "Tintori, Cristina and Veljković, Nevena V. and Veljković, Veljko and Botta, Maurizio", year = "2010", abstract = "A crystal structure of the integrase binding domain (IBD) of the lens epithelium-derived growth factor (LEDGF/p75) in complex with the dimer of the HIV-1 integrase (IN) catalytic core domain (CCD) provides useful information that might help in the understanding of essential protein-protein contacts in HIV-1. However, mutagenic studies indicated that interactions between the full-length proteins were more extensive than the contacts observed in the co-crystal structure of the isolated domains. On the other hand, the biochemical characterization of the interaction between full-length IN and LEDGF/p75 has recently proved that LEDGF/p75 promotes IN tetramerization with two LEDGF/p75 IBD molecules bound to the IN tetramer. This experimental evidence suggests that to obtain a complete structural description of the interactions between the two proteins, the full-length tetrameric structure of IN should be considered. Our aim was to obtain a detailed picture of HIV-1 IN interactions with cellular co-factors that was of general interest, particularly for the development of small molecule IN inhibitors, which mimic the IBD of LEDGF/p75. To this end, we performed bioinformatics analyses to identify protein sequence domains involved in long-range recognition. Subsequently, we applied molecular dynamics techniques to investigate the detailed interactions between the complete tetrameric form of IN and two molecules of the IBD of LEDGF/p75. Our dynamic picture is in agreement with experimental data and, thereby, provides new details of the IN-LEDGF/p75 interaction.", journal = "Proteins: Structure Function and Bioinformatics", title = "Computational studies of the interaction between the HIV-1 integrase tetramer and the cofactor LEDGF/p75: Insights from molecular dynamics simulations and the informational spectrum method", volume = "78", number = "16", pages = "3396-3408", doi = "10.1002/prot.22847" }
Tintori, C., Veljković, N. V., Veljković, V.,& Botta, M.. (2010). Computational studies of the interaction between the HIV-1 integrase tetramer and the cofactor LEDGF/p75: Insights from molecular dynamics simulations and the informational spectrum method. in Proteins: Structure Function and Bioinformatics, 78(16), 3396-3408. https://doi.org/10.1002/prot.22847
Tintori C, Veljković NV, Veljković V, Botta M. Computational studies of the interaction between the HIV-1 integrase tetramer and the cofactor LEDGF/p75: Insights from molecular dynamics simulations and the informational spectrum method. in Proteins: Structure Function and Bioinformatics. 2010;78(16):3396-3408. doi:10.1002/prot.22847 .
Tintori, Cristina, Veljković, Nevena V., Veljković, Veljko, Botta, Maurizio, "Computational studies of the interaction between the HIV-1 integrase tetramer and the cofactor LEDGF/p75: Insights from molecular dynamics simulations and the informational spectrum method" in Proteins: Structure Function and Bioinformatics, 78, no. 16 (2010):3396-3408, https://doi.org/10.1002/prot.22847 . .