This application for competitive renewal of program project grant GM30387 consists of interrelated projects directed by Drs. Roger Kornberg, Michael Levitt, David McKay, Peter Parham and James Spudich. Although, these same investigators are part of the existing program project grant, this proposal presents a significant evolution of focus from cellular structure (membrane channels, receptors and anchors) to molecular structure and function (protein molecules, individually and in complexes, atomic structure of receptors). This change derives from (a) the clear progress made in the present funding period in developing methods and providing pure materials in the quantities needed to study structure on the atomic scale and (b) the recruitment of senior faculty involved in X-ray crystallography (McKay) and macromolecular simulation and modeling (Levitt). The overall organization of the Project consists of four joint projects each involving collaborations between two groups. These projects describe new and original research that is not funded by other sources. The work proposed needs the very high level of expertise provided by each group. In addition, the projects all rely on the essential core facilities involving a tight-knit combination of highly motivated support staff and complicated expensive equipment. Some of the projects relate to systems that are part of a broader study; this provides the necessary underpinnings for functional studies that so nicely complement structural studies (transcription, motility and cellular recognition). As a group, we use a very broad range of different approaches to structural problems extending as they do from theoretical simulation, through X-ray crystallography, electron microscope reconstruction, to chemical, biochemical and genetic engineering methodologies. We expect the Program to foster further interactions and to strengthen the bond between the diverse yet complementary interests of the participants.
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