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Raf kinases are important cancer drug targets. Paradoxically, many B-Raf inhibitors induce the activation of Raf kinases. Cryo-electron microscopy structural analysis of a phosphorylated B-Raf kinase domain dimer in complex with dimeric 14-3-3, at a resolution of ~3.9 angstroms, shows an asymmetric arrangement in which one kinase is in a canonical "active" conformation. The distal segment of the C-terminal tail of this kinase interacts with, and blocks, the active site of the cognate kinase in this asymmetric arrangement. Deletion of the C-terminal segment reduces Raf activity. The unexpected asymmetric quaternary architecture illustrates how the paradoxical activation of Raf by kinase inhibitors reflects an innate mechanism, with 14-3-3 facilitating inhibition of one kinase while maintaining activity of the other. Conformational modulation of these contacts may provide new opportunities for Raf inhibitor development.
This article was published in the following journal.
Name: Science (New York, N.Y.)
Methionine S-adenosyltransferases (MATs) are predominantly homotetramers, comprised of dimers of dimers. The larger, highly conserved intra-dimeric interface harbors two active sites, making the dimer...
Proteasomes are essential in all eukaryotic cells. However, their function and regulation remain considerably elusive, particularly those of less abundant variants. We demonstrate the human 20S protea...
RAF family kinases are RAS-activated switches that initiate signaling through the MAP kinase cascade to control cellular proliferation, differentiation and survival. RAF activity is tightly regulated,...
The translocase of the outer mitochondrial membrane (TOM) is the main entry gate for proteins. Here we use cryo-electron microscopy to report the structure of the yeast TOM core complex at 3.8 Å reso...
Understanding the reaction mechanism of Cas9 is crucial for the application of programmable gene editing. Despite the availability of the structures of Cas9 in apo- and substrate-bound forms, the cata...
Late vitreous hemorrhage in postvitrectomized diabetic eyes may be due to fibrovascular tuft formation in sclerotomy sites. Cryotherapy of sclerotomy sites may prevent bleeding by regressi...
Different techniques of cryotherapy application present divergent responses. The objective was to establish differences between methods of application of ankle cryotherapy on skin surface ...
the purpose of this study is to evaluate the cryotherapy effect by vapocoolant spray to reducing pain during puncture for artérial blood gas
To determine the safety and efficacy of trans-scleral cryotherapy of the peripheral retina in certain low birth-weight infants with retinopathy of prematurity (ROP) for reducing blindness ...
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Molecules that contain multiple active sites which are used to catalyze more than one enzymatic reaction. Proteins in this class generally contain multiple active sites within a single peptide chain and may also contain more than one enzymatically active subunit. They are distinguished from MULTIENZYME COMPLEXES in that their subunits are not found as distinct enzymes.
Congenital or acquired asymmetry of the face.
Proteins that form the structure of the NUCLEAR PORE. They are involved in active, facilitated and passive transport of molecules in and out of the CELL NUCLEUS.
A dimeric sesquiterpene found in cottonseed (GOSSYPIUM). The (-) isomer is active as a male contraceptive (CONTRACEPTIVE AGENTS, MALE) whereas toxic symptoms are associated with the (+) isomer.
The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) TRANSPLANTATION ANTIGENS, genes which control the structure of the IMMUNE RESPONSE-ASSOCIATED ANTIGENS, HUMAN; the IMMUNE RESPONSE GENES which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement.
Bladder Cancer Brain Cancer Breast Cancer Cancer Cervical Cancer Colorectal Head & Neck Cancers Hodgkin Lymphoma Leukemia Lung Cancer Melanoma Myeloma Ovarian Cancer Pancreatic Cancer ...
Pharmacy is the science and technique of preparing as well as dispensing drugs and medicines. It is a health profession that links health sciences with chemical sciences and aims to ensure the safe and effective use of pharmaceutical drugs. The scope of...