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Directed movement is essential for life. Allostery is at the heart of the mechanism that cellular nanomotors use to convert chemical energy into force or movement production. Such molecular motors are essential for a cell to migrate, to divide and organise the intra-cellular traffic between various cellular compartments. The actin-based motors, myosins, are critical for many of these movements, from muscle contraction to cytokinesis, cell compartments communication and sophisticated cellular functions such as hearing. Deficit in these motors can lead to a number of human genetic disorders.
Force is produced by these molecular motors by the conversion of chemical energy derived from ATP hydrolysis into mechanical energy via the interaction with their track, the actin filament. A number of biophysical approaches have provided detailed insights into the mechanism of chemo-mechanical coupling in the actomyosin system. They show how three allosteric sites communicate via relatively small conformational changes in the motor domain that are coupled and amplified by a lever-arm mechanism that produce a working stroke of several nanometers. Structural studies coupled with functional studies is a very powerful technique to identify at atomic resolution a number of communication pathways that are involved at different steps of the motor cycle to couple the nucleotide-binding pocket with the actin interface and the lever arm movement. While ATP binding and hydrolysis are essential for detachment of the motor from its track and its trapping in the pre-stroke conformation, step-wise rebinding to the track triggers controlled release of hydrolysis products (phosphate followed by ADP) upon the working stroke. The current questions regarding the important details of force production will be presented. A reverse motor, myosin VI has been particularly intriguing and informative because of its atypical motility properties, including a reverse directionality. Unpublished structural results from the myosin VI motor not only reveal how its trapping of the hydrolysis products prior to re-attachment to actin stabilize the primed pre-stroke conformation, they also provide insights for the rearrangements triggered by actin to promote Pi release. A new structural state for this myosin with MgADP bound has been crystallized that has all the expected features of the previously unseen Pi release state populated upon motor re-binding to its track. This new structure thus allows visualization for the first time of the structural rearrangements triggered by actin binding that are coupled to force generation and product release at the beginning of the powerstroke.
The current challenges that remain to understand how controlled allosteric transitions tune these motors for distinct specific cellular functions and can control their activity will also be reviewed.