Central to this model is the notion that the correct shape of the substrate can fit into the active site of the enzyme for enabling an efficient and specific catalysis, as observed for enzymes that hydrolyze β-but not α-glycosidic bonds. 1 Throughout the 20 th century, tens of thousands of structures have been solved and deposited in the Protein Data Bank (PDB), supporting again the necessity of a 3-D Page 3 of 116 ACS Paragon Plus Environment Submitted to Chemical Reviews 4 4 structure for functionality. The explanatory power of these 3-D structures continued to reinforce the static view of protein structure that remained unquestioned. In contrast to this view, already in 1958, Koshland suggested the "induced-fit" model based on the observations that some enzymes could act on differently shaped substrates and hence a degree of flexibility is inevitable in function. 2 Furthermore, questions such as "what does the missing electron density in most of the deposited structures in the PDB correspond to?", "why some proteins are highly sensitive in vitro to proteolysis?", and "why some proteins possess a particular behavior during the purification process?" further opened eyes towards flexibility and focused attention on proteins basically distinct from well-known globular proteins. A combined answer to these questions ruled out flexible proteins as artifacts and enlightened the "dark side" of Structural Biology, that of disordered proteins (i.e. proteins that lack 3-D structure). This review provides a detailed description of those proteins that broke the protein rules by their inherent flexibility and peculiar features, now generally termed "intrinsically disordered" proteins (IDPs) or regions (IDRs). This review is intended as a general introduction to the series of thematic reviews in this special issue of Chemical Reviews on IDPs. Our key message is that IDPs possess no well-defined 3-D structure but rather adopt an ensemble of conformations in solution, yet they are functional. A literature survey is provided by summarizing the main aspects of IDPs that led to an exponential increase of interest in these proteins. Moreover, through the different parts of this review, biochemical and biophysical approaches that are frequently used to assess intrinsic disorder are detailed.

It is now half a century since the first crystal structure of a protein (e.g. the atomic structure of myoglobin determined in 1958 by John Kendrew 3 ) was published leading to the "birth" of Structural Biology. Soon after, the field grew rapidly with a dozen of atomic structures of proteins being Page 4 of 116 ACS Paragon Plus Environment