Fig. 7: Changes in the water-mediated networks in Y115H and E497D mutants.

a The crystal structure of WT bovine cardiac myosin bound to Mavacamten at 1.8 Å resolution* (PDB 8QYR) shows the network that stabilizes water molecules near the nucleotide purine group in the active site. Water mediated networks that include residues T124, A182 and N187 stabilise the nucleotide purine group position. b Environment of the myosin active site in the Y115H crystal structure solved at 2.5 Å resolution. The tyrosine to histidine substitution disrupts the water mediated stabilization of the purine group by loss of interactions between H115 and Y134 as well as between H115 and N187. Reorientation of the T124 and N187 side chains occur and no water-based network involving these residues occur to participate in the stabilization of the nucleotide purine group. c Interactions between E497 and R712 in WT human β-cardiac myosin structure solved at 2.6 Å resolution. A water mediated network allows for further interactions between the Relay and the Converter subdomains. d The E497D crystal structure solved at 2.6 Å resolution indicates that weaker interactions occur between D497 and R712. Reorientation of R712 NE disrupts the interactions found in WT with residues of the Converter: bonding with the carbonyl of F709 is maintained by NE reorientation whereas the water mediated binding with K762 and E500 is lost. In Supplementary Fig. S14, a more detailed version of this figure including the distance annotations is provided.