The goals of the structural biology core are threefold: (1) to determine structures of the HIV envelope glycoprotein in its various conformations (and especially in the unliganded state found on the surface of a mature virion), in order to have as complete a """"""""molecular movie"""""""" of its conformational transitions as possible; (2) to engage in collaborative structure determinations with investigators in the CHAVI project (in particular to answer questions about how molecular context influences immunogenicity of gp120 variable loops) or to help organize such collaborations with other laboratories when appropriate; (3) to communicate the complex picture of envelope conformational transformations to the rest of the HIV community and in particular to the other investigators in this CHAVI consortium.
Specific aims i nclude: (1) generating stabilized forms of unliganded HIV-1 gp120 for structural studies, by introducing disulfide bonds based on the recently determined structure of unliganded SIV gp120; (2) using the results of the first aim to produce stabilized gp140 trimers for structural studies; (3) using the results of the first two aims to analyze the immunogenic properties of the HIV envelope protein in its unliganded conformation. Depending on the outcome of other experiments in the CHAVI consortium, structures will be determined for certain Fab fragments from """"""""broadly"""""""" neutralizing mAbs, in complex with peptide antigens or with gp120 or gp140 bearing the appropriate epitopes. There will be an ongoing effort to communicate the complexities of envelope conformational changes, through development of an interactive molecular animation that incorporates new structural data as they emerge.
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