Binding of TPX2 to Aurora A Alters Substrate and Inhibitor Interactions.

@article{citeulike:1585234, abstract = {The Aurora kinases are a family of serine/threonine kinases involved in mitosis. The expression of AurA is ubiquitous and cell cycle regulated. It is overexpressed in many tumor types, including breast, colon, and ovarian. TPX2 is a binding partner and activator of AurA. A fragment of TPX2 (residues 1-43) has been shown to be sufficient for binding, kinase activation, and protection from dephosphorylation. We have shown that the addition of TPX2(1-43) increases the catalytic efficiency of AurA. While TPX2 binding has no effect on the turnover number of AurA and does not change the reaction mechanism (characterized here to be a rapid equilibrium random mechanism), it increases the binding affinity of both ATP and a peptide substrate. We have also demonstrated differences in the inhibitor structure-activity relationship (SAR) in the presence or absence of TPX2(1-43). To better understand the differential SAR, we carried out computer modeling studies to gain insight into the effect of TPX2 on the binding interactions between AurA and inhibitors. Our working hypothesis is that TPX2 binding decreases the size and accessibility of a hydrophobic pocket, adjacent to the ATP site, to inhibitors.}, address = {Enzymology and Mechanistic Pharmacology, Biological Reagents and Assay Development, Computational and Structural Chemistry, Oncology Biology, and Medicinal Chemistry, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426.}, author = {Anderson, Kelly and Yang, Jingsong and Koretke, Kristin and Nurse, Kelvin and Calamari, Amy and Kirkpatrick, Robert B. and Patrick, Denis and Silva, Domingos and Tummino, Peter J. and Copeland, Robert A. and Lai, Zhihong }, citeulike-article-id = {1585234}, doi = {http://dx.doi.org/10.1021/bi7011355}, issn = {0006-2960}, journal = {Biochemistry}, keywords = {aurora, sar, structure, tpx2, vx-680}, month = {August}, posted-at = {2007-08-23 11:21:06}, priority = {2}, title = {Binding of TPX2 to Aurora A Alters Substrate and Inhibitor Interactions.}, url = {http://dx.doi.org/10.1021/bi7011355}, year = {2007} }

TY - JOUR ID - citeulike:1585234 L3 - citeulike-article-id:1585234 TI - Binding of TPX2 to Aurora A Alters Substrate and Inhibitor Interactions. JF - Biochemistry AD - Enzymology and Mechanistic Pharmacology, Biological Reagents and Assay Development, Computational and Structural Chemistry, Oncology Biology, and Medicinal Chemistry, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426. SN - 0006-2960 N2 - The Aurora kinases are a family of serine/threonine kinases involved in mitosis. The expression of AurA is ubiquitous and cell cycle regulated. It is overexpressed in many tumor types, including breast, colon, and ovarian. TPX2 is a binding partner and activator of AurA. A fragment of TPX2 (residues 1-43) has been shown to be sufficient for binding, kinase activation, and protection from dephosphorylation. We have shown that the addition of TPX2(1-43) increases the catalytic efficiency of AurA. While TPX2 binding has no effect on the turnover number of AurA and does not change the reaction mechanism (characterized here to be a rapid equilibrium random mechanism), it increases the binding affinity of both ATP and a peptide substrate. We have also demonstrated differences in the inhibitor structure-activity relationship (SAR) in the presence or absence of TPX2(1-43). To better understand the differential SAR, we carried out computer modeling studies to gain insight into the effect of TPX2 on the binding interactions between AurA and inhibitors. Our working hypothesis is that TPX2 binding decreases the size and accessibility of a hydrophobic pocket, adjacent to the ATP site, to inhibitors. KW - aurora KW - sar KW - structure KW - tpx2 KW - vx-680 AU - Anderson, Kelly AU - Yang, Jingsong AU - Koretke, Kristin AU - Nurse, Kelvin AU - Calamari, Amy AU - Kirkpatrick, Robert AU - Patrick, Denis AU - Silva, Domingos AU - Tummino, Peter AU - Copeland, Robert AU - Lai, Zhihong PY - 2007/08/18/ UR - http://dx.doi.org/10.1021/bi7011355 ER -