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Emeritus Group Holmes
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Research
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Molecular mechanisms of muscle contraction, mechanics of nucleotide-dependent enzymes, actin, myosin, kinesin, cytoskeleton, creatine kinase.
A primary aim of the Department of Biophysics since its foundation in 1968 has been to understand in physiochemical terms the molecular mechanism by which muscles produce force. Muscle contraction involves the cyclic interaction of the proteins myosin and actin, often pictured as the rowing of the myosin and actin filaments past each other, using the hydrolysis of ATP as a source of energy. We study the structures of actin and myosin at atomic and near-atomic resolution by protein crystallography, electron microscopy and X-ray fibre diffraction. As a supplementary technique for studying mobility we also use NMR.
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We study myosins from various sources and with a varity of bound nucleotide analogues, also in combination with site-directed mutagenesis. A biochemistry group which specializes in the expression of proteins in the cellular slime mould dictyostelium uses enzyme kinetics and in vitro motility assays to guage the effects of mutagenesis. The most interesting cases are then analysed by x-ray crystallography. This project is part of an international collaboration. The last two years have seen dramatic progress in our understanding of the molecular basis of muscle contraction and indeed we now have considerable understanding of the processes involved in myosin-based motility. The crystallography goup studies other proteins as well, in particular on those which, like myosin, involve the processing of nucleotides.
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Figure 1 (taken from Muscle Contraction) shows the Lymn-Taylor cycle (Lymn and Taylor 1971): the myosin cross bridge is bound to actin in rigor 45°- position - down [1]. ATP binds which leads to very fast dissociation from actin [2]. The hydrolysis of ATP to ADP and Pi leads to a return of the myosin cross bridge to the 90° up position whereupon it rebinds to actin [3]. This leads to release of the products and return to [1]. In the last step actin is rowed past myosin.
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