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 to provide 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 on antagonism of HIV envelope function in cell entry. Our technical focus is on x-ray crystallography, so as to determine structures at sufficient resolution to develop mechanistic insights, but associated binding experiments and computations will also be performed. Our specific aims comprise structural analyses of complexes of HIV gp120 with chemically derivatized CD4, structural analyses of complexes of HIV gp120 with other candidate inhibitory molecules, structural studies of HIV gp120 interactions with other natural binding partners besides CD4, and innovative computational analyses of gp120 plasticity. We build not only on our recent experience in this program, but also on our earlier structural investigations of human CD4, HIV gp120s, and associated antibodies. We have adopted or developed both appropriate expression systems for making the required proteins and also appropriate assays for following inhibitory action. Interaction with other elements of the Program Project is essential for this project. We interact most intimately with Project 3 on chemistry (Smith) and Project 5 on virology (Sodroski), but also significantly with Project 2 on peptidomimetics and miniproteins (Chaiken), Project 4 on thermodynamics (Friere), and with both the computation core (LaLonde) and the protein core (Chaiken).