The Experts below are selected from a list of 132 Experts worldwide ranked by ideXlab platform
Marcie A Glicksman - One of the best experts on this subject based on the ideXlab platform.
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type ii kinase inhibitors show an unexpected inhibition mode against parkinson s disease linked lrrk2 mutant g2019s
Biochemistry, 2013Co-Authors: Samantha Bender, Gregory D Cuny, Woody Sherman, Marcie A GlicksmanAbstract:A number of well-known type II inhibitors (ATP-noncompetitive) that bind kinases in their DFG-out conformation were tested against wild-type LRRK2 and the most common Parkinson’s disease-linked mutation, G2019S. We found that traditional type II inhibitors exhibit surprising variability in their inhibition mechanism between the wild type (WT) and the G2019S mutant of LRRK2. The type II kinase inhibitors were found to work in an ATP-competitive fashion against the G2019S mutant, whereas they appear to follow the expected noncompetitive mechanism against WT. Because the G2019S mutation lies in the DXG motif (DYG in LRRK2 but DFG in most other kinases) of the activation loop, we explored the structural consequence of the mutation on loop dynamics using an enhanced sampling method called metadynamics. The simulations suggest that the G2019S mutation stabilizes the DYG-in state of LRRK2 through a series of hydrogen bonds, leading to an increase in the Conformational Barrier between the active and inactive form...
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Type II Kinase Inhibitors Show an Unexpected Inhibition Mode against Parkinson’s Disease-Linked LRRK2 Mutant G2019S
Biochemistry, 2013Co-Authors: Min Liu, Gregory D Cuny, Woody Sherman, Marcie A Glicksman, Samantha A. Bender, Soumya S. RayAbstract:A number of well-known type II inhibitors (ATP-noncompetitive) that bind kinases in their DFG-out conformation were tested against wild-type LRRK2 and the most common Parkinson’s disease-linked mutation, G2019S. We found that traditional type II inhibitors exhibit surprising variability in their inhibition mechanism between the wild type (WT) and the G2019S mutant of LRRK2. The type II kinase inhibitors were found to work in an ATP-competitive fashion against the G2019S mutant, whereas they appear to follow the expected noncompetitive mechanism against WT. Because the G2019S mutation lies in the DXG motif (DYG in LRRK2 but DFG in most other kinases) of the activation loop, we explored the structural consequence of the mutation on loop dynamics using an enhanced sampling method called metadynamics. The simulations suggest that the G2019S mutation stabilizes the DYG-in state of LRRK2 through a series of hydrogen bonds, leading to an increase in the Conformational Barrier between the active and inactive form...
Soumya S. Ray - One of the best experts on this subject based on the ideXlab platform.
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Type II Kinase Inhibitors Show an Unexpected Inhibition Mode against Parkinson’s Disease-Linked LRRK2 Mutant G2019S
Biochemistry, 2013Co-Authors: Min Liu, Gregory D Cuny, Woody Sherman, Marcie A Glicksman, Samantha A. Bender, Soumya S. RayAbstract:A number of well-known type II inhibitors (ATP-noncompetitive) that bind kinases in their DFG-out conformation were tested against wild-type LRRK2 and the most common Parkinson’s disease-linked mutation, G2019S. We found that traditional type II inhibitors exhibit surprising variability in their inhibition mechanism between the wild type (WT) and the G2019S mutant of LRRK2. The type II kinase inhibitors were found to work in an ATP-competitive fashion against the G2019S mutant, whereas they appear to follow the expected noncompetitive mechanism against WT. Because the G2019S mutation lies in the DXG motif (DYG in LRRK2 but DFG in most other kinases) of the activation loop, we explored the structural consequence of the mutation on loop dynamics using an enhanced sampling method called metadynamics. The simulations suggest that the G2019S mutation stabilizes the DYG-in state of LRRK2 through a series of hydrogen bonds, leading to an increase in the Conformational Barrier between the active and inactive form...
Woody Sherman - One of the best experts on this subject based on the ideXlab platform.
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type ii kinase inhibitors show an unexpected inhibition mode against parkinson s disease linked lrrk2 mutant g2019s
Biochemistry, 2013Co-Authors: Samantha Bender, Gregory D Cuny, Woody Sherman, Marcie A GlicksmanAbstract:A number of well-known type II inhibitors (ATP-noncompetitive) that bind kinases in their DFG-out conformation were tested against wild-type LRRK2 and the most common Parkinson’s disease-linked mutation, G2019S. We found that traditional type II inhibitors exhibit surprising variability in their inhibition mechanism between the wild type (WT) and the G2019S mutant of LRRK2. The type II kinase inhibitors were found to work in an ATP-competitive fashion against the G2019S mutant, whereas they appear to follow the expected noncompetitive mechanism against WT. Because the G2019S mutation lies in the DXG motif (DYG in LRRK2 but DFG in most other kinases) of the activation loop, we explored the structural consequence of the mutation on loop dynamics using an enhanced sampling method called metadynamics. The simulations suggest that the G2019S mutation stabilizes the DYG-in state of LRRK2 through a series of hydrogen bonds, leading to an increase in the Conformational Barrier between the active and inactive form...
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Type II Kinase Inhibitors Show an Unexpected Inhibition Mode against Parkinson’s Disease-Linked LRRK2 Mutant G2019S
Biochemistry, 2013Co-Authors: Min Liu, Gregory D Cuny, Woody Sherman, Marcie A Glicksman, Samantha A. Bender, Soumya S. RayAbstract:A number of well-known type II inhibitors (ATP-noncompetitive) that bind kinases in their DFG-out conformation were tested against wild-type LRRK2 and the most common Parkinson’s disease-linked mutation, G2019S. We found that traditional type II inhibitors exhibit surprising variability in their inhibition mechanism between the wild type (WT) and the G2019S mutant of LRRK2. The type II kinase inhibitors were found to work in an ATP-competitive fashion against the G2019S mutant, whereas they appear to follow the expected noncompetitive mechanism against WT. Because the G2019S mutation lies in the DXG motif (DYG in LRRK2 but DFG in most other kinases) of the activation loop, we explored the structural consequence of the mutation on loop dynamics using an enhanced sampling method called metadynamics. The simulations suggest that the G2019S mutation stabilizes the DYG-in state of LRRK2 through a series of hydrogen bonds, leading to an increase in the Conformational Barrier between the active and inactive form...
Gregory D Cuny - One of the best experts on this subject based on the ideXlab platform.
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type ii kinase inhibitors show an unexpected inhibition mode against parkinson s disease linked lrrk2 mutant g2019s
Biochemistry, 2013Co-Authors: Samantha Bender, Gregory D Cuny, Woody Sherman, Marcie A GlicksmanAbstract:A number of well-known type II inhibitors (ATP-noncompetitive) that bind kinases in their DFG-out conformation were tested against wild-type LRRK2 and the most common Parkinson’s disease-linked mutation, G2019S. We found that traditional type II inhibitors exhibit surprising variability in their inhibition mechanism between the wild type (WT) and the G2019S mutant of LRRK2. The type II kinase inhibitors were found to work in an ATP-competitive fashion against the G2019S mutant, whereas they appear to follow the expected noncompetitive mechanism against WT. Because the G2019S mutation lies in the DXG motif (DYG in LRRK2 but DFG in most other kinases) of the activation loop, we explored the structural consequence of the mutation on loop dynamics using an enhanced sampling method called metadynamics. The simulations suggest that the G2019S mutation stabilizes the DYG-in state of LRRK2 through a series of hydrogen bonds, leading to an increase in the Conformational Barrier between the active and inactive form...
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Type II Kinase Inhibitors Show an Unexpected Inhibition Mode against Parkinson’s Disease-Linked LRRK2 Mutant G2019S
Biochemistry, 2013Co-Authors: Min Liu, Gregory D Cuny, Woody Sherman, Marcie A Glicksman, Samantha A. Bender, Soumya S. RayAbstract:A number of well-known type II inhibitors (ATP-noncompetitive) that bind kinases in their DFG-out conformation were tested against wild-type LRRK2 and the most common Parkinson’s disease-linked mutation, G2019S. We found that traditional type II inhibitors exhibit surprising variability in their inhibition mechanism between the wild type (WT) and the G2019S mutant of LRRK2. The type II kinase inhibitors were found to work in an ATP-competitive fashion against the G2019S mutant, whereas they appear to follow the expected noncompetitive mechanism against WT. Because the G2019S mutation lies in the DXG motif (DYG in LRRK2 but DFG in most other kinases) of the activation loop, we explored the structural consequence of the mutation on loop dynamics using an enhanced sampling method called metadynamics. The simulations suggest that the G2019S mutation stabilizes the DYG-in state of LRRK2 through a series of hydrogen bonds, leading to an increase in the Conformational Barrier between the active and inactive form...
Michael R. Topp - One of the best experts on this subject based on the ideXlab platform.
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Conformational Barrier crossing in the water dimer cluster of coumarin 151 studied by infrared optical double-resonance spectroscopy
Chemical Physics Letters, 2001Co-Authors: Yu Chen, Michael R. ToppAbstract:Abstract Vibronically induced Conformational relaxation is reported between two distinct structures of the jet-cooled cluster coumarin 151/(H2O)2. The process involves transfer of the water dimer in the electronically excited state over a distance of ≈8 A between sites on the coumarin molecule, governed by an activation energy of 60 cm −1 .
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Spectroscopy of jet-cooled water complexes with coumarin 151: Observation of vibronically induced Conformational Barrier crossing
The Journal of Physical Chemistry A, 1998Co-Authors: Brian A. Pryor, Phillip M. Palmer, Peter M. Andrews, Mitchell B. Berger, Michael R. ToppAbstract:Coumarin 151, when complexed 1:1 by a water molecule in a supersonic jet, develops two sets of resonances, based on features displaced by −45 cm-1 (species A) and −690 cm-1 (species B) from the unc...
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Electronic coupling and Conformational Barrier crossing of 9,9’‐bifluorenyl studied in a supersonic jet
The Journal of Chemical Physics, 1994Co-Authors: Philip G. Smith, S. Gnanakaran, Andrew J. Kaziska, Andrea L. Motyka, S. M. Hong, Robin M. Hochstrasser, Michael R. ToppAbstract:Fluorescence excitation, dispersed fluorescence, and picosecond time‐resolved fluorescence spectroscopies have been used to study the dimeric molecule 9,9’‐bifluorenyl, isolated under supersonic jet conditions. The excitation spectrum reveals a splitting in several principal resonances of the S0→S1 excitation spectrum, which can be attributed to electronic coupling between the two fluorenyl moieties. The splitting, which for different vibronic transitions correlates with Franck–Condon factors, is consistent with an exciton model that includes higher electronic states. The splitting is reasonably well reproduced by a multipole interaction potential. Calculations have verified that the electron exchange coupling is small. Furthermore, the relative intensities of the resonances allow an estimate of the equilibrium geometry, suggesting that the molecular long axes have an angular displacement of 60°–70°, consistent with the geometry found by x‐ray diffraction. A most interesting feature of this species is tha...