Fig. 6: HCM mutations Y115H and E497D alter local interactions in the human β-cardiac PPS structure.
a Localization of residues Y115 and E497 in the motor domain (MD). Regions involved in Y115-Y134-nucleotide interactions are the N-term (grey); Transducer (dark green) and ADP.Pi (orange). Regions involved in E497-R712 interactions are the Relay helix (yellow) and Converter (lime). b, c Electronic density comparison for the Y115H mutation: b Y115 in the X-ray crystal structure of the human cardiac myosin WT MD (PDB 9I8P) and c H115 in the X-ray crystal structure of the human cardiac myosin H115 mutant MD (PDB 9HTF). d, e Electronic density comparison for the E497D mutation: d E497 in the X-ray crystal structure of the human cardiac myosin WT MD (PDB 9I8P) and e D497 in the X-ray crystal structure of the human cardiac myosin D497 mutant MD (PDB 9HTG). f Interactions between Y115/H115, Y134 and the nucleotide (blue lines, H-bonds; grey lines, other distances). No changes in conformation are observed for the ADP.Pi nor for Y134. The Y115-Y134 H-bond is not maintained in the Y115H mutant as the shorter imidazole side chain cannot reach the Y134 hydroxyl group, in contrast to Y115’s larger phenol side chain. g Interactions between E497/D497 and R712 (blue lines, H-bonds; orange lines, salt bridge; grey lines, other distances). E497-R712 forms a strong ionic bond in the WT structure. While the salt bridge between D497 and R712 is maintained in E497D through a change of conformation of R712, it is subsequently weakened as only one of D497’s oxygens is in position to form the ionic bond. The D497-R712 interaction is mediated through Y501 that forms H-bonds with both D497 and R712. The Y501 side chain changes its orientation to accommodate this bonding.
