Considerable progress has been made towards establishing the structural basis of muscle contraction and molecular basis of motility itself over the last three years. This has been accomplished through the structure determination of chicken skeletal myosin subfragment-1 in its apo-form and several nucleotide complexes for a truncated myosin molecule. These studies, in combination with high resolution electron microscopy, have lead to a structural model for muscle contraction in which conformational changes associated with the nucleotide binding site are amplified through the light chain binding motif to generate a powerstroke. This model suggested how the nucleotide binding site communicates with the actin binding site through a series of coupled domain movements. In the last year the focus of our studies at CHESS has been directed towards understanding the structural basis of the catalytic mechanism through the determination of the structure of wide range of myosin:nucleotide complexes. Data for more than ten nucleotide complexes has been or will be shortly collected. This includes classic nucleotide analogs such as ATPgS, AMPPNP, ADP and GMPPNP, together with spin-labelled ADP.BeFx and a series of non-nucleotide analogs that support movement. Together these complexes will define the structure of the myosin motor domain at two distinct states in the contractile cycle and should lead to an improved model for understanding ATP hydrolysis and myosin-based motility.
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