• Kinase
  • Structure-Activity Relationship Studies of Mitogen Activated Protein Kinase Interacting Kinase (MNK) 1 and 2 and BCR-ABL1 Inhibitors Targeting Chronic Myeloid Leukemic Cells. (nih.gov)
  • We show that the atypical secretory kinase family with sequence similarity 20, member B (Fam20B) phosphorylates the initiating xylose residue in the proteoglycan tetrasaccharide linkage region, and that this event functions as a molecular switch to regulate subsequent glycosaminoglycan assembly. (jove.com)
  • Recent studies have revealed that most of the BRAF inhibitors can induce dimerization and paradoxically stimulate enzyme transactivation by conferring an active conformation in the second monomer of the kinase dimer. (rsc.org)
  • The emerging connections between inhibitor binding and BRAF kinase domain dimerization have suggested a molecular basis of the activation mechanism in which BRAF inhibitors may allosterically modulate the stability of the dimerization interface and affect the organization of residue interaction networks in BRAF kinase dimers. (rsc.org)
  • The results of this study highlight previously unexplored relationships between types of BRAF inhibitors, inhibitor-induced changes in the residue interaction networks and allosteric modulation of the kinase activity. (rsc.org)
  • Pathway inhibition of the RAS-driven MAPK pathway using small-molecule kinase inhibitors has been a key focus for treating cancers driven by oncogenic RAS, yet significant clinical responses are lacking. (aacrjournals.org)
  • For example, lung cancer cells exhibiting dysregulated EGFR activity caused by somatic mutations are specifically sensitive to EGFR tyrosine kinase inhibitors ( 4-6 ). (aacrjournals.org)
  • resistance mechanisms
  • This mini-review is focused on the various mechanisms of resistance to the currently available anti-TB drugs and provides perspective on novel strategies and lead scaffolds/compounds aimed at inhibiting/overcoming these resistance mechanisms. (frontiersin.org)
  • It is therefore important to know the activity of antimicrobial agents against the pathogens associated with diseases being treated empirically and the effect of resistance mechanisms on in vivo activity. (springer.com)
  • The current status of resistance mechanisms found in Haemophilus infl uenzae and Moraxella catarrhalis against the antimicrobial agents recommended for empiric and directed treatment of the diseases caused by these pathogens form the basis of this review. (springer.com)
  • To determine whether additional adaptive resistance mechanisms may coexist, we characterized global phosphoproteomic changes after MEK inhibitor selumetinib (AZD6244) treatment in KRAS -mutant A427 and A549 lung adenocarcinoma cell lines employing mass spectrometry-based phosphoproteomics. (aacrjournals.org)
  • peptide
  • Classical lock and key inhibitors such as phosphoramidon and bestatin bind tightly by approximating the transition state of the hydrolysis of the peptide, preventing it from acting on other substrates. (wikipedia.org)
  • inhibition
  • Despite different binding sites and concentrations required for half-maximal inhibition-ranging from nanomolar for the Q site inhibitor atpenin A5 to millimolar for the succinate analog malonate-all inhibitors modulated ROS production in the same ambivalent fashion: they promoted the generation of superoxide at the Q o site of complex III under conditions of "oxidant-induced reduction" but attenuated ROS generated at complex I due to reverse electron transfer. (aspetjournals.org)
  • All inhibitors showed these ambivalent effects independent of the presence of K + . These findings suggest a direct modulation of mitochondrial ROS generation during cardioprotection via complex II inhibition and question the recently proposed role of complex II as a regulatory component of the putative mitochondrial K ATP channel. (aspetjournals.org)
  • The effect of atpenin A5 was independent of complex II inhibition, and the authors suggested that opening of the putative mitoK ATP channel is the underlying mechanism. (aspetjournals.org)
  • The structures and accompanying cell-based fusion assays with inhibitors provide insight into the molecular mechanism for the inhibition of MeV-mediated fusion, which would help us conquer MeV-induced neurodegenerative diseases. (pnas.org)
  • However, preclinical studies have shown MEK or PI3K inhibition in lung cancer leads to variable responses, and a subset of KRAS -mutant cancer cells are refractory to MEK or PI3K inhibitors ( 7-9 ). (aacrjournals.org)
  • interfere
  • This study suggests a mechanism by which BRAF inhibitors could promote or interfere with the paradoxical activation of BRAF kinases, which may be useful in informing discovery efforts to minimize the unanticipated adverse biological consequences of these therapeutic agents. (rsc.org)
  • protein
  • Counter-regulatory mechanisms include the inherent GTPase activity of the heterotrimeric Gα subunits, the GTPase activating activity of regulators of G-protein signaling (RGS) proteins, and the multistage process of receptor desensitization (reviewed in ref. 12 ). (aacrjournals.org)
  • In this work, we integrated structural bioinformatics analysis, molecular dynamics and binding free energy simulations with the protein structure network analysis of the BRAF crystal structures to determine dynamic signatures of BRAF conformations in complexes with different types of inhibitors and probe the mechanisms of the inhibitor-induced dimerization and paradoxical activation. (rsc.org)
  • Due to the physical interactions between the labeled molecule and a protein, biochemical methods can be used to determine the toxicity, efficacy, and the mechanism of action of the drug. (wikipedia.org)
  • This provides an insight at a possible mechanism of action, as it is known what certain functional components of the drug are responsible for interacting with a certain area on a protein, thus, leading to a therapeutic effect. (wikipedia.org)
  • Based on analysis of the molecular properties of the RecA system, Cox concluded that the data "provide compelling evidence that the primary mission of RecA protein is DNA repair. (wikipedia.org)
  • Protein inhibitors such as α2-macroglobulin are known to work with metalloproteinases. (wikipedia.org)
  • In the design of these inhibitors, the basic protein backbone of collagen is maintained but the amide bond is replaced with a zinc-binding group. (wikipedia.org)
  • reveal
  • Collectively, our findings suggest that GalT-II function is impaired by loss of Fam20B-dependent xylose phosphorylation and reveal a previously unappreciated mechanism for regulation of proteoglycan biosynthesis. (jove.com)
  • common mechanism
  • The most common mechanism of resistance in Mtb is the alteration of the target's binding site through the accumulation of mutations. (frontiersin.org)
  • Dimerization-induced activation has emerged as a common mechanism of allosteric regulation in BRAF kinases, which play an important role in growth factor signalling and human diseases. (rsc.org)
  • Cells
  • In this study, we explored the effect of MPT0B169 on apoptosis in AML HL60 and NB4 cells and MDR1-mediated taxol-resistant HL60/TaxR cells and the underlying mechanism. (springer.com)
  • In the present work, we studied the molecular mechanisms by which sodium butyrate sensitizes cancer cells towards cisplatin. (biomedcentral.com)
  • sequence
  • The search process induces stretching of the DNA duplex, which enhances sequence complementarity recognition (a mechanism termed conformational proofreading). (wikipedia.org)
  • effect
  • In this study, we have analyzed the effect of different cardioprotective complex II inhibitors on the mitochondrial production of reactive oxygen species (ROS) because ROS seem to be essential for signaling during preconditioning to prevent ischemia/reperfusion injury. (aspetjournals.org)
  • complex
  • We have shown that ROS generation at Q o site of complex III is maximal if the Q-pool is partially reduced implying that superoxide is generated by reverse electron transfer from reduced heme b L to molecular oxygen with ubiquinone serving as a redox mediator ( Dröse and Brandt, 2008 ). (aspetjournals.org)
  • activation
  • These mechanisms of counter-regulation normally buffer against the aberrant or sustained activation that might occur in the presence of constant ligand stimulation. (aacrjournals.org)