Abstract
Advances in protein structure determination, led by the structural genomics initiatives have increased the proportion of novel folds deposited in the Protein Data Bank. However, these structures are often not accompanied by functional annotations with experimental confirmation. In this review, we reassess the meaning of structural novelty and examine its relevance to the complexity of the structure-function paradigm. Recent advances in the prediction of protein function from structure are discussed, as well as new sequence-based methods for partitioning large, diverse superfamilies into biologically meaningful clusters. Obtaining structural data for these functionally coherent groups of proteins will allow us to better understand the relationship between structure and function.