Proteus in the World of Proteins: Conformational Changes in Protein Kinases

2010 ◽  
Vol 343 (4) ◽  
pp. 193-206 ◽  
Author(s):  
Matthias Rabiller ◽  
Matthäus Getlik ◽  
Sabine Klüter ◽  
André Richters ◽  
Sandra Tückmantel ◽  
...  
Keyword(s):  
Protein Kinases ◽  
Conformational Changes ◽  
The World

Protein kinases and their therapeutic exploitation

2007 ◽  
Vol 35 (1) ◽  
pp. 7-11 ◽  
Author(s):  
L. Johnson
Keyword(s):  
Protein Kinases ◽  
Conformational Changes ◽  
Glycogen Phosphorylase ◽  
Molecular Level ◽  
Enzyme Activation ◽  
Phosphorylase Kinase ◽  
Binding Properties ◽  
Cyclin Dependent Kinases ◽  
Substrate Protein ◽  
Potential Therapeutic Application

This review focuses on the recognition properties of protein kinases at the molecular level. Phosphorylation of the substrate protein by a protein kinase can result in enzyme activation or inhibition, conformational changes that change recognition properties, or the creation of a surface with distinct binding properties. Protein kinases have become important targets for the development of inhibitors with potential therapeutic application. Various examples are considered in this review, and I discuss our own work on glycogen phosphorylase and phosphorylase kinase, and the structures of proteins involved with the cell cycle, including cyclins and cyclin-dependent kinases.

Calmodulin conformational changes in the activation of protein kinases

2002 ◽  
Vol 30 (2) ◽  
pp. 55-61 ◽  
Author(s):  
K. Török
Keyword(s):  
Energy Transfer ◽  
Protein Kinases ◽  
Conformational Changes ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Activation Process ◽  
Dependent Protein ◽  
Peptide Complexes ◽  
Muscle Myosin ◽  
Kinetics Of

The conformation of Ca2+/calmodulin changes from extended when free in solution to compact when bound in peptide complexes. The extent and kinetics of calmodulin compaction in association with Ca2+/calmodulin-dependent protein kinases (CaMKs), as well as target peptides, were investigated by fluorescence, resonance energy transfer and stopped-flow kinetics. Compaction of Ca2+/ calmodulin labelled with resonance energy-transfer probes in association with target peptides was rapid (>350 s−1). With the target enzymes smooth-muscle myosin light-chain kinase, CaMKIV and αcCaMKII, the rates of calmodulin compaction were one-two orders of magnitude lower compared with those of the peptides and in the case of αCaMKII, ATP binding and Thr286 auto-phosphorylation were required for calmodulin compaction. In the absence of nucleotides, Ca2+/calmodulin bound to αCaMKII in extended conformations, initially probably attached by one lobe only. Kinetic data suggest that in the activation process of Ca2+/ calmodulin-dependent protein kinases, productive as well as unproductive complexes are formed. The formation of productive complexes with Ca2+/calmodulin thus may determine the rate of activation.

Review Lecture: Protein phosphorylation and hormone action

1988 ◽  
Vol 234 (1275) ◽  
pp. 115-144 ◽  
Keyword(s):  
Protein Kinases ◽  
Conformational Changes ◽  
Protein Phosphatases ◽  
Second Messengers ◽  
Cellular Processes ◽  
Extracellular Signals ◽  
Steady State Levels ◽  
Pleiotropic Actions ◽  
Signalling Systems ◽  
Chemical Mediators

Many key regulatory proteins exist in cells as either a phosphorylated or a dephosphorylated form, their steady-state levels of phosphorylation reflecting the relative activities of the protein kinases and protein phosphatases that catalyse the interconversion process. Phosphorylation of seryl or threonyl (and occasionally tyrosyl) residues triggers small conformational changes in these proteins that alter their biological proper­ties. Hormones and other extracellular signals transmit information to the interior of the cell by activating transmembrane signalling systems that control the production of a relatively small number of chemical mediators, termed ‘second messengers’. These substances regulate the activities of protein kinases and phosphatases, and so alter the phos­phorylation states of many intracellular proteins, accounting for the di­versity of action of hormones. In this lecture I review recent work which demonstrates that a wide variety of cellular processes are controlled by relatively few protein kinases and protein phosphatases with pleiotropic actions. These enzymes provide the basis of an interlocking network that allows extracellular signals to coordinate biochemical functions.

scholarly journals Dynamics of human protein kinases linked to drug selectivity

2018 ◽  
Author(s):  
Warintra Pitsawong ◽  
Vanessa Buosi ◽  
Renee Otten ◽  
Roman V. Agafonov ◽  
Adelajda Zorba ◽  
...  
Keyword(s):  
Protein Dynamics ◽  
Protein Kinases ◽  
Conformational Changes ◽  
Drug Targets ◽  
Active Sites ◽  
Kinase Inhibitors ◽  
Drug Binding ◽  
Inhibition Mechanism ◽  
Aurora A ◽  
Drug Selectivity

AbstractProtein kinases are major drug targets, but the development of highly-selective inhibitors has been challenging due to the similarity of their active sites. The observation of distinct structural states of the fully-conserved Asp-Phe-Gly (DFG) loop has put the concept of conformational selection for the DFG-state at the center of kinase drug discovery. Recently, it was shown that Gleevec selectivity for the Tyr-kinases Abl was instead rooted in conformational changes after drug binding. Here, we investigate whether protein dynamics after binding is a more general paradigm for drug selectivity by characterizing the binding of several approved drugs to the Ser/Thr-kinase Aurora A. Using a combination of biophysical techniques, we propose a universal drug-binding mechanism, that rationalizes selectivity, affinity and long on-target residence time for kinase inhibitors. These new concepts, where protein dynamics in the drug-bound state plays the crucial role, can be applied to inhibitor design of targets outside the kinome.eLife digestThe Ser/Thr kinase Aurora A is an important target for the development of new anticancer therapies. A longstanding question is how to specifically and effectively inhibit only this kinase in a background of over 550 protein kinases with very similar structures. To this end, understanding the inhibition mechanism of Aurora A by different drugs is essential. Here, we characterize the kinetic mechanism of three distinct kinase drugs, Gleevec (Imatinib), Danusertib (PHA739358) and AT9283 (Pyrazol-4-yl Urea) for Aurora A. We show that inhibitor affinities do not rely exclusively on the recognition of a specific conformation of the Asp-Phe-Gly loop of the kinase. Our quantitative kinetics data put forward an opposing mechanism in which a slow conformational change after drug binding (i.e., induced-fit step) dictates drug affinity.

scholarly journals May SARS-CoV-2 Diffusion Be Favored by Alkaline Aerosols and Ammonia Emissions?

Atmosphere ◽  
2020 ◽  
Vol 11 (9) ◽  
pp. 995
Author(s):  
Maurizio Manigrasso ◽  
Carmela Protano ◽  
Ettore Guerriero ◽  
Matteo Vitali ◽  
Pasquale Avino
Keyword(s):  
Conformational Changes ◽  
Hepatitis Virus ◽  
Common Factor ◽  
Virus Transmission ◽  
Viral Envelope ◽  
Target Cells ◽  
Ammonia Emissions ◽  
Murine Hepatitis Virus ◽  
Livestock Farming ◽  
The World

Ammonia is a common factor linking air in bat caves and air pollution in the proximity of agricultural fields treated with livestock farming sewage and slaughterhouses, where important clusters of COVID-19 have recently been reported all over the world. Such a commonality has a further connection with the known behavior of some viruses of the coronavirus family, such as the murine hepatitis virus, whose spike glycoprotein (S) can be triggered to a membrane-binding conformation at pH 8.0. Within the airborne route of virus transmission, with particular relevance for crowded and enclosed environments, these observations have prompted a hypothesis that may represent a contributing cause to interpret the geographical variability of the virus diffusion and the surging rise of COVID-19 cases in slaughterhouses all over the world. The hypothesis is that, in these environments, the SARS-CoV-2 S protein may find on a fraction of the airborne particles an alkaline pH, favorable to trigger the conformational changes, needed to induce the fusion of the viral envelope with the plasma membrane of the target cells.

Ligand-Induced Conformational Changes in Cyclic Nucleotide Phosphodiesterases and Cyclic Nucleotide-Dependent Protein Kinases

Methods ◽  
1998 ◽  
Vol 14 (1) ◽  
pp. 81-92 ◽  
Author(s):  
Sharron H. Francis ◽  
Der-Ming Chu ◽  
Melissa K. Thomas ◽  
Alfreda Beasley ◽  
Kennard Grimes ◽  
...  
Keyword(s):  
Protein Kinases ◽  
Conformational Changes ◽  
Cyclic Nucleotide ◽  
Cyclic Nucleotide Phosphodiesterases ◽  
Dependent Protein ◽  
Nucleotide Phosphodiesterases

A pragmatist philosophy of psychological science and its implications for replication

2018 ◽  
Vol 41 ◽  
Author(s):  
Ana Gantman ◽  
Robin Gomila ◽  
Joel E. Martinez ◽  
J. Nathan Matias ◽  
Elizabeth Levy Paluck ◽  
...  
Keyword(s):  
William James ◽  
Mental Processes ◽  
Psychological Science ◽  
Behavioral Measurement ◽  
The World ◽  
Pragmatist Philosophy

AbstractA pragmatist philosophy of psychological science offers to the direct replication debate concrete recommendations and novel benefits that are not discussed in Zwaan et al. This philosophy guides our work as field experimentalists interested in behavioral measurement. Furthermore, all psychologists can relate to its ultimate aim set out by William James: to study mental processes that provide explanations for why people behave as they do in the world.

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