The standard orientation and numbering systems for protease structures of Wolfram Bode

The so-called standard orientation was gradually developed by Wolfram Bode and his group as a key concept for the visualization of protease active sites. It was derived from the linear Schechter-Berger system of substrate and inhibitor binding to cysteine, metallo and serine proteases, whereby the N-terminus of peptides is placed on the left and the C-terminus on the right. For the first time, the standard orientation was defined for human thrombin, the central protease of blood coagulation. Along the present review, this orientation will be the golden thread to follow the outstanding studies of the Bode group on proteases over four decades. It can even be applied to catalytic domains of proteases with buried active sites by displaying only relevant molecular elements. Another useful concept is the chymotrypsinogen numbering, which was extensively used by this group for related serine proteases. Thus, the N-terminal residue is always number 16 and the catalytic triad comprises His57, Asp102, and Ser195. Thereby, residues critical for function, insertions and deletions are more evident, as well as evolutionary relationships. Groundbreaking studies on structure and function of serine proteases will be presented and discussed, as well as similarly important research of metalloproteinases and several cysteine proteases.