The impact of X-ray crystallography and NMR on intracellular calcium signal transduction by EF-hand proteins: crossing the threshold from structure to biology and medicine.

The use of x-ray crystallography and solution nuclear magnetic resonance (NMR) spectroscopy has revolutionized our understanding of the transduction of intracellular calcium signals into cellular responses. Indeed, the ability to cross a critical threshold from basic descriptive structural biochemistry to real-world applications in therapeutics and biotechnology now looms on the experimental horizon. The ~500 atomic resolution structures determined by x-ray and NMR approaches and deposited in the Protein Data Bank, many of which are of complexes of EF-hand proteins with peptide fragments of cellular targets, have yielded an extremely thorough description for how EF-hand proteins respond to the binding of calcium. Although this database of structures is a powerful structural tool to describe EF-hand protein function, it is limited in its ability to have a significant impact on biology and medicine because the structural effects on the downstream target are not determined. The opportunity that now lies before us is to extend this EF-hand-centric structural information so that the alterations in the target proteins are defined and the structural basis for functional consequences downstream is understood.