The long-term goal is to understand biomolecular organization and function particularly at critical intermolecular interfaces in biology, at various structural levels. One focus is on integral transmembrane proteins: Structural studies of acetylcholine receptors, fundamental to all vertebrate neuromuscular communication are to define the arrangment of Alpha2BetaGammaDelta subunits, to define the polypeptide folding within each subunit using immuno-electron microscopy and low dose imaging of frozen hydrated samples, to define main immunogenic regions in the disease myasthenia gravis, and to define ligand and toxin sites. Changes in structure upon activation will be analyzed to define the mechanisms of channel formation, subunit assembly, and activation of the channel and disensitization. A long-term goal is to understand the insertion of membrane protein sequences, and formation of multimeric membrane proteins. Crystallized colicin Ia and possibly Ib, 80,000 dalton soluble proteins that make transmembrane ion channels across membranes, are to be defined in their presumed soluble conformation, at atomic resolution using x-ray crystallography; chemical studies are to define mechanisms of transmembrane channel formation in these single hit lethal antibacterial molecules. Various interferons have been or are being crystallized as precursor to crystallographic analysis. The structure will be a template for studies of the critical molecular surface, alteration of the surface by site specific mutagenesis, and generation of new anti-viral functions aimed at defining the mechanisms of anti-viral action. Highest resolution studies of trypsin and trypsinogen are to give fundamental new basic information about the dynamics, solvation, and reaction chemistry of this allosteric protein system. The goal is an intimate understanding of energetic factors which determine protein stability, allosteric effects, and the role of dynamics and orientation in this protein.
NIH ExPorter
NIH ExPorter