Wei Zhang - Exploring the Intermediate States of ADP-ATP Exchange:

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      Publication Details (including relevant citation   information):


          J Phys Chem       B. 2010 Dec 30. [Epub ahead of print]   



             While mitotic kinesins have attracted signi ficant   attention in recent years as   new anticancer drug targets, the underlying mechanism of   kinesin-catalyzed ATP hydrolysis is still under investigation.   Crystal structures of Eg5, one of the best-studied kinesins, have   been solved in both ADP-bound and ATP-bound states. However, it   is still extremely challenging to experimentally obtain   structural information on the functionally important intermediate   states, such as the nucleotide free (apo)   and the initial ATP-kinesin    collision state. Systematic molecular dynamics simulations were   performed in this study to mimic different   nucleotide  binding   states and explore the critical structural and dynamic variations   during ADP-ATP   exchange. Clear conformational changes from   ADP-like  toward  ATP-like  were observed   fromthe simulation results. A highly conserved residue   Arg234  was found   to  play a key   role during the nucleotide exchange. This positively charged   residue acted as the hub  of a hydrogen-bond   network that  extended   the effect   of γ-phosphoryl   group to both SW-I and SW-II regions. Comparison among the   results of different   nucleotide  binding   states indicated that the existence of γ-phosphoryl   was immediately sensed at the initial ATP collision state by   residue Ser233,    and this initial interaction induced the back-door  opening and   the front-door  closing of the   nucleotide binding pocket. In addition,  several   potential allosteric binding sites were identified   through combination of correlation analysis and binding site   mapping  approaches   based on the simulated apo  ensemble, which   provided additional targeting sites for novel allosteric Eg5   inhibition. These molecular   simulation results provided not only a better understanding of   Eg5-catalyzed ATP hydrolysis but also the structural basis for   design of novel specific   Eg5 inhibitors as anticancer therapeutic agents. 

      Address (URL): http://www.ncbi.nlm.nih.gov/pubmed/21192710