A model for a main element of the active site of skeletal muscle myosin is presented that relates directly to the 92 amino acid fragment (p 10) of myosin recently described by Elzinga & Collins (1977). In this model, the substrate, an eight-membered cyclic complex of MgATP, fits tightly into a 16 amino acid segment of p 10 and interacts with seven of its amino acids. A main feature of the model is the important role played by the one molecule of N τ -methylhistidine † † N t -methylhistidine is 2-amino-3-(1′methyl-4′-imidazolyl)propanoic acid. that is present in each myosin heavy chain. At the site, it is postulated that this rare amino acid functions as a donor ligand to Mg 2+. Once N τ -methylhistidine is put in place next to the metal, the other amino acids that appear to form a pocket come easily into position around the MgATP. These amino acids with their postulated functions are: tyrosine 72, which through a Mg-bound water, or perhaps directly, is attached to the Mg; histidine 76, which donates a proton to the P γ of ATP; lysine 78, which binds electrostatically to P β of ATP; phenylalanines 80 and 81, which flank the purine ring of ATP; and aspartate 66, which forms a hydrogen bond to the 6-amino group of adenine. The Mg-coordination role ascribed to N τ -methylhistidine 69 in skeletal muscle myosin could be taken by histidine 69 in cardiac myosin and in other muscle myosins that do not contain the methylated amino acid. The choice of p 10 to contain a main element of the active site is based on: (a) the presence in p 10 of the essential sulfhydryl groups, SH1 and SH2, whose modification affects the ATPase activity of myosin; (b) the presence in ρ 10 of N τ -methylhistidine, an unusual amino acid whose methylation in skeletal muscle we take as an indicator for a special function at the active site; (c) the position of p 10 in the primary structure near the junction between subfragment 1 and subfragment 2 (the hinge region) where, we postulate, enzymatic events at the active site are coupled to movements of the hinge that occur during contraction; (d) indications that the DTNB light chain, probably involved in regulation, is also near the hinge; (e) the effects of MgATP at the active site on the chemical reactivity of three SH groups (SH1, SH2 and SH3) located near the hinge; and (f) the effect of hinge cleavage on the oxygen exchange reaction catalyzed at the active site. The correlation of all these observations forms the basis for our placement of part of the active site on p 10 near the subfragment 1-subfragment 2 hinge.