The general structural features of the motor region of myosin superfamily members are now well established, as is a subset of the structural and kinetic transitions of the actin-myosin catalytic cycle. Not yet visualized are the structural rearrangements triggered by actin binding that are coupled to force generation and product release. In this review we describe the recent progress in understanding these missing components of the mechanism of chemomechanical transduction by myosin motors. These insights come from a combination of kinetic and single-molecule studies on multiple classes of myosins, with additional insights from contracting muscle fibers. These recent studies have explored the effects of intermediate and high loads on the kinetics of the actin-bound myosin state transitions. We also describe studies that delineate how some classes of myosin motors are adapted for processive movement on actin.

The molecular motor, myosin, undergoes conformational changes in order to convert chemical energy into force production. Based on kinetic and structural considerations, we assert that three crystal forms of the myosin V motor delineate the conformational changes that myosin motors undergo upon detachment from actin. First, a motor domain structure demonstrates that nucleotide‐free myosin V adopts a specific state (rigor‐like) that is not influenced by crystal packing. A second structure reveals an actomyosin state that favors rapid release of ADP, and differs from the rigor‐like state by a P‐loop rearrangement. Comparison of these structures with a third structure, a 2.0 Å resolution structure of the motor bound to an ATP analog, illuminates the structural features that provide communication between the actin interface and nucleotide‐binding site. Paramount among these is a region we name the transducer, which is composed of the seven‐stranded β‐sheet and associated loops and linkers. Reminiscent of the β‐sheet distortion of the F1‐ATPase, sequential distortion of this transducer region likely controls sequential release of products from the nucleotide pocket during force generation.

We have determined the structure of the intact scallop myosin head, containing both the motor domain and the lever arm, in the nucleotide-free state and in the presence of MgADP⋅VO4, corresponding to the transition state. These two new structures, together with the previously determined structure of scallop S1 complexed with MgADP (which we interpret as a detached ATP state), reveal three conformations of an intact S1 obtained from a single isoform. These studies, together with new crystallization results, show how the conformation of the motor depends on the nucleotide content of the active site. The resolution of the two new structures (≈4 Å) is sufficient to establish the relative positions of the subdomains and the overall conformation of the joints within the motor domain as well as the position of the lever arm. Comparison of available crystal structures from different myosin isoforms and truncated constructs in either the nucleotide-free or transition states indicates that the major features within the motor domain are relatively invariant in both these states. In contrast, the position of the lever arm varies significantly between different isoforms. These results indicate that the heavy-chain helix is pliant at the junction between the converter and the lever arm and that factors other than the precise position of the converter can influence the position of the lever arm. It is possible that this pliant junction in the myosin head contributes to the compliance known to be present in the crossbridge.