Dynamics-Driven Allostery in Protein Kinases

Kornev, Alexandr P.; Taylor, Susan S.

doi:10.1016/j.tibs.2015.09.002

Cited by 256 publications

(294 citation statements)

References 105 publications

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“…At the interface of the two lobes lies the active site of the kinase that includes the nucleotide (ADP or ATP) binding site, the magnesium binding site (DFG motif), and the phospho-acceptor site (activation segment). The motions between the lobes are controlled by the flexible hinge and enable recruitment of the substrate and release of the product 46 . The catalytically active conformation of the kinase domain requires a closed conformation between the two lobes, an unfolded activation segment and the αC-helix of the N-terminal lobe fixed into the IN position to bring the catalytic residues into a productive distance and orientation (FIG.…”

Section: Structural Insight Into Raf Activationmentioning

confidence: 99%

New perspectives for targeting RAF kinase in human cancer

2017

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The discovery that a subset of human tumours is dependent on mutationally deregulated BRAF kinase intensified the development of RAF inhibitors to be used as potential therapeutics. The US Food and Drug Administration (FDA)-approved second-generation RAF inhibitors vemurafenib and dabrafenib have elicited remarkable responses and improved survival of patients with BRAF-V600E/K melanoma, but their effectiveness is limited by resistance. Beyond melanoma, current clinical RAF inhibitors show modest efficacy when used for colorectal and thyroid BRAF-V600E tumours or for tumours harbouring BRAF alterations other than the V600 mutation. Accumulated experimental and clinical evidence indicates that the complex biochemical mechanisms of RAF kinase signalling account both for the effectiveness of RAF inhibitors and for the various mechanisms of tumour resistance to them. Recently, a number of next-generation RAF inhibitors, with diverse structural and biochemical properties, have entered preclinical and clinical development. In this Review, we discuss the current understanding of RAF kinase regulation, mechanisms of inhibitor action and related clinical resistance to these drugs. The recent elucidation of critical structural and biochemical aspects of RAF inhibitor action, combined with the availability of a number of structurally diverse RAF inhibitors currently in preclinical and clinical development, will enable the design of more effective RAF inhibitors and RAF-inhibitor-based therapeutic strategies, tailored to different clinical contexts.

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Section: Structural Insight Into Raf Activationmentioning

confidence: 99%

New perspectives for targeting RAF kinase in human cancer

2017

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“…This community network model can reflect the conformational entropy of the molecule and has been recently gaining appreciation as a way to understand dynamics-based protein allostery in various proteins including thrombin (23), Tec kinases (24), and also PKA (22). By building on our earlier models for community-based networks for the wtPKA (22,25), we provide a dynamic conformational entropy-based explanation for the disruption of catalytic activity in PKA by a single point mutation that lies far from the active site. We carry out this comparison for the catalytically competent ATP-bound states of both wild-type and Y204A structures.…”

Section: Significancementioning

confidence: 99%

Mutation of a kinase allosteric node uncouples dynamics linked to phosphotransfer

Ahuja

Kornev

McClendon

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The expertise of protein kinases lies in their dynamic structure, wherein they are able to modulate cellular signaling by their phosphotransferase activity. Only a few hundreds of protein kinases regulate key processes in human cells, and protein kinases play a pivotal role in health and disease. The present study dwells on understanding the working of the protein kinase-molecular switch as an allosteric network of “communities” composed of congruently dynamic residues that make up the protein kinase core. Girvan–Newman algorithm-based community maps of the kinase domain of cAMP-dependent protein kinase A allow for a molecular explanation for the role of protein conformational entropy in its catalytic cycle. The community map of a mutant, Y204A, is analyzed vis-à-vis the wild-type protein to study the perturbations in its dynamic profile such that it interferes with transfer of the γ-phosphate to a protein substrate. Conventional biochemical measurements are used to ascertain the effect of these dynamic perturbations on the kinetic profiles of both proteins. These studies pave the way for understanding how mutations far from the kinase active site can alter its dynamic properties and catalytic function even when major structural perturbations are not obvious from static crystal structures.

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“…Abl, like many other kinases, is known to function as a graded rather than simply an “on” and “off” switch 19,20 . Given the dynamic nature of protein kinases 21–23 insight into their conformational and energetic landscape 24–26 is required to fully understand the underlying mechanisms of regulation and how kinases respond to diverse signals.…”

Section: Introductionmentioning

confidence: 99%

Atomic view of the energy landscape in the allosteric regulation of Abl kinase

Saleh

Rossi

2017

Nat Struct Mol Biol

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The activity of protein kinases is often regulated in an intramolecular fashion by signaling domains, which feature several phosphorylation or protein-docking sites. How kinases integrate such distinct binding and signaling events to regulate their activities is unclear, especially in quantitative terms. We have used NMR spectroscopy to show how structural elements within the Abl regulatory module (RM) form synergistically a multilayered allosteric mechanism that enables Abl kinase to function as a finely-tuned switch. We dissected the structure and energetics of the regulatory mechanism to precisely measure the effect of various stimuli, activating or inhibiting, on the Abl kinase activity. The data provide the mechanistic basis for explaining genetic observations and reveal a novel activator region within Abl. Our findings show that drug-resistant mutations in the Abl RM exert their allosteric effect by promoting the activated state of Abl and not by decreasing the drug affinity for the kinase.

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Dynamics-Driven Allostery in Protein Kinases

Cited by 256 publications

References 105 publications

New perspectives for targeting RAF kinase in human cancer

New perspectives for targeting RAF kinase in human cancer

Mutation of a kinase allosteric node uncouples dynamics linked to phosphotransfer

Atomic view of the energy landscape in the allosteric regulation of Abl kinase

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