A modeled structure of an aptamer-gp120 complex provides insight into the mechanism of HIV-1 neutralization
| dc.contributor.author | Joubert, Marisa K | |
| dc.contributor.author | Kinsley, Nichole | |
| dc.contributor.author | Capovilla, Alexio | |
| dc.contributor.author | Sewell, B Trevor | |
| dc.contributor.author | Jaffer, Mohamed A | |
| dc.contributor.author | Khati, Makobetsa | |
| dc.date.accessioned | 2016-07-27T12:43:16Z | |
| dc.date.available | 2016-07-27T12:43:16Z | |
| dc.date.issued | 2010 | |
| dc.date.updated | 2016-07-12T15:59:10Z | |
| dc.description.abstract | The HIV-1 envelope glycoprotein, gp120, is a key target for a class of drugs called entry inhibitors. Here we used molecular modeling to construct a three-dimensional model of an anti-gp120 RNA aptamer, B40t77, alone and in complex with gp120. An initial model of B40t77 was built from the predicted secondary structure and then subjected to a combination of energy minimization and molecular dynamics. To model the B40t77-gp120 complex, we docked the B40t77 predicted structure onto the CD4-induced epitope of the gp120 crystal structure. A series of gp120 point mutations in the predicted B40t77-gp120 interface were measured for their binding affinity for B40t77 by surface plasmon resonance. According to the model, of the 10 gp120 amino acids that showed a reduction in the level of binding when mutated to alanine, all of them are modeled as making direct contact with B40t77 as part of a hydrogen bonding network. Comparison by electron microscopy of the B40t77-gp120 complex with gp120 alone revealed that only the longest dimension of the complex significantly increased in length, in a manner consistent with the predicted model. Binding assays revealed that B40t77 can weaken the binding of gp120 to the monoclonal antibodies B6, B12, and 2G12, none of which have binding sites that overlap with B40t77, as well as strengthen the binding to the antibody 19b. Thus, B40t77 may induce distant conformational changes in gp120 that disrupt its association with host cells and may suggest a mechanism for aptamer neutralization of HIV-1. | en_ZA |
| dc.identifier | http://dx.doi.org/10.1021/bi100301k | |
| dc.identifier.apacitation | Joubert, M. K., Kinsley, N., Capovilla, A., Sewell, B. T., Jaffer, M. A., & Khati, M. (2010). A modeled structure of an aptamer-gp120 complex provides insight into the mechanism of HIV-1 neutralization. <i>Biochemistry</i>, http://hdl.handle.net/11427/20892 | en_ZA |
| dc.identifier.chicagocitation | Joubert, Marisa K, Nichole Kinsley, Alexio Capovilla, B Trevor Sewell, Mohamed A Jaffer, and Makobetsa Khati "A modeled structure of an aptamer-gp120 complex provides insight into the mechanism of HIV-1 neutralization." <i>Biochemistry</i> (2010) http://hdl.handle.net/11427/20892 | en_ZA |
| dc.identifier.citation | Joubert, M. K., Kinsley, N., Capovilla, A., Sewell, B. T., Jaffer, M. A., & Khati, M. (2010). A Modeled Structure of an Aptamer− gp120 Complex Provides Insight into the Mechanism of HIV-1 Neutralization. Biochemistry, 49(28), 5880-5890. | en_ZA |
| dc.identifier.issn | 0006-2960 | en_ZA |
| dc.identifier.ris | TY - Journal Article AU - Joubert, Marisa K AU - Kinsley, Nichole AU - Capovilla, Alexio AU - Sewell, B Trevor AU - Jaffer, Mohamed A AU - Khati, Makobetsa AB - The HIV-1 envelope glycoprotein, gp120, is a key target for a class of drugs called entry inhibitors. Here we used molecular modeling to construct a three-dimensional model of an anti-gp120 RNA aptamer, B40t77, alone and in complex with gp120. An initial model of B40t77 was built from the predicted secondary structure and then subjected to a combination of energy minimization and molecular dynamics. To model the B40t77-gp120 complex, we docked the B40t77 predicted structure onto the CD4-induced epitope of the gp120 crystal structure. A series of gp120 point mutations in the predicted B40t77-gp120 interface were measured for their binding affinity for B40t77 by surface plasmon resonance. According to the model, of the 10 gp120 amino acids that showed a reduction in the level of binding when mutated to alanine, all of them are modeled as making direct contact with B40t77 as part of a hydrogen bonding network. Comparison by electron microscopy of the B40t77-gp120 complex with gp120 alone revealed that only the longest dimension of the complex significantly increased in length, in a manner consistent with the predicted model. Binding assays revealed that B40t77 can weaken the binding of gp120 to the monoclonal antibodies B6, B12, and 2G12, none of which have binding sites that overlap with B40t77, as well as strengthen the binding to the antibody 19b. Thus, B40t77 may induce distant conformational changes in gp120 that disrupt its association with host cells and may suggest a mechanism for aptamer neutralization of HIV-1. DA - 2010 DB - OpenUCT DP - University of Cape Town J1 - Biochemistry LK - https://open.uct.ac.za PB - University of Cape Town PY - 2010 SM - 0006-2960 T1 - A modeled structure of an aptamer-gp120 complex provides insight into the mechanism of HIV-1 neutralization TI - A modeled structure of an aptamer-gp120 complex provides insight into the mechanism of HIV-1 neutralization UR - http://hdl.handle.net/11427/20892 ER - | en_ZA |
| dc.identifier.uri | http://hdl.handle.net/11427/20892 | |
| dc.identifier.vancouvercitation | Joubert MK, Kinsley N, Capovilla A, Sewell BT, Jaffer MA, Khati M. A modeled structure of an aptamer-gp120 complex provides insight into the mechanism of HIV-1 neutralization. Biochemistry. 2010; http://hdl.handle.net/11427/20892. | en_ZA |
| dc.language | eng | en_ZA |
| dc.publisher | American Chemical Society | en_ZA |
| dc.publisher.institution | University of Cape Town | |
| dc.source | Biochemistry | en_ZA |
| dc.source.uri | http://www.biochemj.org/ | |
| dc.title | A modeled structure of an aptamer-gp120 complex provides insight into the mechanism of HIV-1 neutralization | en_ZA |
| dc.type | Journal Article | en_ZA |
| uct.type.filetype | Text | |
| uct.type.filetype | Image | |
| uct.type.publication | Research | en_ZA |
| uct.type.resource | Article | en_ZA |