Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
AAPS J
2019 Dec 18;221:14. doi: 10.1208/s12248-019-0399-6.
Show Gene links
Show Anatomy links
Structural Characterization of the Aurora Kinase B "DFG-flip" Using Metadynamics.
Lakkaniga NR
,
Balasubramaniam M
,
Zhang S
,
Frett B
,
Li HY
.
???displayArticle.abstract???
Aurora kinase B (AKB), a Ser/Thr kinase that plays a crucial role in mitosis, is overexpressed in several cancers. Clinical inhibitors targeting AKB bind to the active DFG "in" conformation of the kinase. It would be beneficial, however, to understand if AKB is susceptible to type II kinase inhibitors that bind to the inactive, DFG "out" conformation, since type II inhibitors achieve higher kinome selectivity and higher potency in vivo. The DFG "out" conformation of AKB is not yet experimentally determined which makes the design of type II inhibitors exceedingly difficult. An alternate approach is to simulate the DFG "out" conformation from the experimentally determined DFG "in" conformation using atomistic molecular dynamics (MD) simulation. In this work, we employed metadynamics (MTD) approach to simulate the DFG "out" conformation of AKB by choosing the appropriate collective variables. We examined structural changes during the DFG-flip and determined the interactions crucial to stabilize the kinase in active and inactive states. Interestingly, the MTD approach also identified a unique transition state (DFG "up"), which can be targeted by small molecule inhibitors. Structural insights about these conformations is essential for structure-guided design of next-generation AKB inhibitors. This work also emphasizes the usefulness of MTD simulations in predicting macromolecular conformational changes at reduced computational costs.
Barducci,
Well-tempered metadynamics: a smoothly converging and tunable free-energy method.
2008, Pubmed
Barducci,
Well-tempered metadynamics: a smoothly converging and tunable free-energy method.
2008,
Pubmed
Callegari,
Metadynamics Simulations Distinguish Short- and Long-Residence-Time Inhibitors of Cyclin-Dependent Kinase 8.
2017,
Pubmed
Carmena,
The chromosomal passenger complex (CPC): from easy rider to the godfather of mitosis.
2012,
Pubmed
Carrera,
The conserved lysine of the catalytic domain of protein kinases is actively involved in the phosphotransfer reaction and not required for anchoring ATP.
1993,
Pubmed
Chieffi,
Aurora B expression directly correlates with prostate cancer malignancy and influence prostate cell proliferation.
2006,
Pubmed
Cohen,
The origins of protein phosphorylation.
2002,
Pubmed
Dar,
The evolution of protein kinase inhibitors from antagonists to agonists of cellular signaling.
2011,
Pubmed
Dodson,
Crystal structure of an Aurora-A mutant that mimics Aurora-B bound to MLN8054: insights into selectivity and drug design.
2010,
Pubmed
Endicott,
The structural basis for control of eukaryotic protein kinases.
2012,
Pubmed
Ensing,
Metadynamics as a tool for exploring free energy landscapes of chemical reactions.
2006,
Pubmed
Fadri-Moskwik,
Aurora B is regulated by acetylation/deacetylation during mitosis in prostate cancer cells.
2012,
Pubmed
Harrington,
VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo.
2004,
Pubmed
Hartsink-Segers,
Aurora kinases in childhood acute leukemia: the promise of aurora B as therapeutic target.
2013,
Pubmed
Hunter,
A thousand and one protein kinases.
1987,
Pubmed
Johnson,
Active and inactive protein kinases: structural basis for regulation.
1996,
Pubmed
Knight,
Conservation, variability and the modeling of active protein kinases.
2007,
Pubmed
Kornev,
Surface comparison of active and inactive protein kinases identifies a conserved activation mechanism.
2006,
Pubmed
Laio,
Escaping free-energy minima.
2002,
Pubmed
Levinson,
A Src-like inactive conformation in the abl tyrosine kinase domain.
2006,
Pubmed
Li,
Conformational Transition Pathways of Epidermal Growth Factor Receptor Kinase Domain from Multiple Molecular Dynamics Simulations and Bayesian Clustering.
2014,
Pubmed
Manning,
The protein kinase complement of the human genome.
2002,
Pubmed
Marampon,
Close correlation between MEK/ERK and Aurora-B signaling pathways in sustaining tumorigenic potential and radioresistance of gynecological cancer cell lines.
2014,
Pubmed
Meng,
Predicting the Conformational Variability of Abl Tyrosine Kinase using Molecular Dynamics Simulations and Markov State Models.
2018,
Pubmed
Meng,
Computational study of the "DFG-flip" conformational transition in c-Abl and c-Src tyrosine kinases.
2015,
Pubmed
Nolen,
Regulation of protein kinases; controlling activity through activation segment conformation.
2004,
Pubmed
Park,
Molecular Dynamics Analysis of Binding of Kinase Inhibitors to WT EGFR and the T790M Mutant.
2016,
Pubmed
Porcelli,
Aurora kinase B inhibition reduces the proliferation of metastatic melanoma cells and enhances the response to chemotherapy.
2015,
Pubmed
Roskoski,
Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes.
2016,
Pubmed
Schindler,
Structural mechanism for STI-571 inhibition of abelson tyrosine kinase.
2000,
Pubmed
Sessa,
Structure of Aurora B-INCENP in complex with barasertib reveals a potential transinhibitory mechanism.
2014,
Pubmed
,
Xenbase
Sessa,
Mechanism of Aurora B activation by INCENP and inhibition by hesperadin.
2005,
Pubmed
,
Xenbase
Shan,
Transitions to catalytically inactive conformations in EGFR kinase.
2013,
Pubmed
Shan,
A conserved protonation-dependent switch controls drug binding in the Abl kinase.
2009,
Pubmed
Shaw,
Atomic-level characterization of the structural dynamics of proteins.
2010,
Pubmed
Sini,
Pharmacological Profile of BI 847325, an Orally Bioavailable, ATP-Competitive Inhibitor of MEK and Aurora Kinases.
2016,
Pubmed
Sultan,
Millisecond dynamics of BTK reveal kinome-wide conformational plasticity within the apo kinase domain.
2017,
Pubmed
Takeshita,
Aurora-B overexpression is correlated with aneuploidy and poor prognosis in non-small cell lung cancer.
2013,
Pubmed
Tang,
Aurora kinases: novel therapy targets in cancers.
2017,
Pubmed
Taylor,
Protein kinases: evolution of dynamic regulatory proteins.
2011,
Pubmed
Treiber,
Ins and outs of kinase DFG motifs.
2013,
Pubmed
Tribello,
A self-learning algorithm for biased molecular dynamics.
2010,
Pubmed
Tuncel,
Nuclear Aurora B and cytoplasmic Survivin expression is involved in lymph node metastasis of colorectal cancer.
2012,
Pubmed
Vader,
The chromosomal passenger complex: guiding Aurora-B through mitosis.
2006,
Pubmed
Vashisth,
"DFG-flip" in the insulin receptor kinase is facilitated by a helical intermediate state of the activation loop.
2012,
Pubmed
Wu,
Inhibition of Aurora B by CCT137690 sensitizes colorectal cells to radiotherapy.
2014,
Pubmed
Yamauchi,
Aurora B inhibitor barasertib and cytarabine exert a greater-than-additive cytotoxicity in acute myeloid leukemia cells.
2013,
Pubmed
Zhang,
Elevated Aurora B expression contributes to chemoresistance and poor prognosis in breast cancer.
2015,
Pubmed
Zhang,
An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor.
2006,
Pubmed
Zhang,
Mechanistic insight into the functional transition of the enzyme guanylate kinase induced by a single mutation.
2015,
Pubmed
Zhou,
CS2164, a novel multi-target inhibitor against tumor angiogenesis, mitosis and chronic inflammation with anti-tumor potency.
2017,
Pubmed
