Principal investigator/Program Director (Last, First, Middle): Chaiken, Irwin M. / Hendrickson, Wayne A.DESCRIPTION:This project is an investigation into the structural biology of HIV entry inhibition. Our overall objective is toprovide an atomic-level understanding of opportunities for intervention in processes of cell entry by HIV.Continued work toward this goal will be conducted as Project 1 in the context of a Program Project onantagonism of HIV envelope function in cell entry. Our technical focus is on x-ray crystallography, so as todetermine structures at sufficient resolution to develop mechanistic insights, but associated bindingexperiments and computations will also be performed.
Our specific aims comprise structural analyses ofcomplexes of HIV gp120 with chemically derivatized CD4, structural analyses of complexes of HIV gp120with other candidate inhibitory molecules, structural studies of HIV gp120 interactions with other naturalbinding partners besides CD4, and innovative computational analyses of gp120 plasticity. We build not onlyon our recent experience in this program, but also on our earlier structural investigations of human CD4, HIVgp120s, and associated antibodies. We have adopted or developed both appropriate expression systemsfor making the required proteins and also appropriate assays for following inhibitory action. Interaction withother elements of the Program Project is essential for this project. We interact most intimately with Project 3on chemistry (Smith) and Project 5 on virology (Sodroski), but also significantly with Project 2 onpeptidomimetics and miniproteins (Chaiken), Project 4 on thermodynamics (Friere), and with both thecomputation core (LaLonde) and the protein core (Chaiken).
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