Fig. 1. Stapling in MEK1. (a) (Top) In nature, Lan is formed enzymatically between amino acids and in peptides but not proteins. (Middle) Stapling methods used in peptides can stabilize extracted motifs and large cycles can bridge some proteins, albeit often with extended bridges or linkers and/or through use of reactive, non-canonical amino acids (ncAAs) that may not be driven by reactivity that reports on conformation; SDM = site directed mutagenesis. In this work: we propose Lan as a minimal staple that might, through a set of cyclization rules, report upon conformations that enable stapling chemistries, likely in minimal motifs more likely to be under conformational control of relevance to function. (b) Enzymatic phosphorylation at sites Ser218, Ser222 in its activation loop is the primary mode of activation of MEK1. (c) The Raf-MEK-ERK MAPK signaling cascade.