Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Keywords: INHIBITORS ; KINASES ; pharmacology ; PROTEIN ; KINASE ; INHIBITOR ; protein kinase ; PROTEIN-KINASE ; PKA ; PROTEIN-KINASES
    Type of Publication: Book chapter
    Signatur Availability
    BibTip Others were also interested in ...
  • 2
    Keywords: CANCER ; CELLS ; INHIBITOR ; INVASION ; tumor ; CELL ; COMBINATION ; Germany ; INHIBITION ; KINASE ; PATHWAY ; THERAPY ; DISEASE ; DISEASES ; SITE ; PROTEIN ; COMPLEX ; COMPLEXES ; MECHANISM ; DOMAIN ; BINDING ; PHOSPHORYLATION ; protein kinase ; PROTEIN-KINASE ; treatment ; CATALYTIC SUBUNIT ; inactivation ; FIBER ; ADHESION ; ATP ; CELL-ADHESION ; crystal structure ; CRYSTAL-STRUCTURE ; MUSCLE ; PKA ; PROTEIN-KINASES
    Abstract: Protein kinases require strict inactivation to prevent spurious cellular signaling; overactivity can cause cancer or other diseases and necessitates selective inhibition for therapy. Rho-kinase is involved in such processes as tumor invasion, cell adhesion, smooth muscle contraction, and formation of focal adhesion fibers, as revealed using inhibitor Y-27632. Another Rho-kinase inhibitor, HA-1077 or Fasudil, is currently used in the treatment of cerebral vasospasm; the related nanomolar inhibitor H-1152P improves on its selectivity and potency. We have determined the crystal structures of HA-1077, H-1152P, and Y-27632 in complexes with protein kinase A (PKA) as a surrogate kinase to analyze Rho-kinase inhibitor binding properties. Features conserved between PKA and Rho-kinase are involved in the key binding interactions, while a combination of residues at the ATP binding pocket that are unique to Rho-kinase may explain the inhibitors' Rho-kinase selectivity. Further, a second H-1152P binding site potentially points toward PKA regulatory domain interaction modulators
    Type of Publication: Journal article published
    PubMed ID: 14656443
    Signatur Availability
    BibTip Others were also interested in ...
  • 3
    Keywords: PEPTIDE ; CANCER ; INHIBITOR ; Germany ; KINASE ; TOOL ; DISEASE ; SITE ; PROTEIN ; DRUG ; TRANSDUCTION ; COMPLEX ; COMPLEXES ; MECHANISM ; DOMAIN ; INDUCTION ; BINDING ; BIOLOGY ; PROTEIN-KINASE ; signal transduction ; SIGNAL ; VARIANTS ; DISCOVERY ; MOLECULE ; CATALYTIC SUBUNIT ; SIGNAL-TRANSDUCTION ; ATP ; CRYSTAL-STRUCTURE ; PKA ; PROTEIN-KINASE-C ; FLEXIBILITY ; max ; DOMAINS ; INHIBITORS ; POTENT ; VARIANT ; PHASE-III ; SELECTIVE INHIBITORS ; STAUROSPORINE ; STRUCTURAL BASIS ; UCN-01
    Abstract: As the key mediators of eukaryotic signal transduction, the protein kinases often cause disease, and in particular cancer, when disregulated. Appropriately selective protein kinase inhibitors are sought after as research tools and as therapeutic drugs; several have already proven valuable in clinical use. The AGC subfamily protein kinase C (PKC) was identified early as a cause of cancer, leading to the discovery of a variety of PKC inhibitors. Despite its importance and early discovery, no crystal structure for PKC has yet been reported. Therefore, we have co-crystallized PKC inhibitor bisindolyl maleimide 2 (BIM2) with PKA variants to study its binding interactions. BIM2 co-crystallized as an asymmetric pair of kinase-inhibitor complexes. In this asymmetric unit, the two kinase domains have different lobe configurations, and two different inhibitor conformers bind in different orientations. One kinase molecule ( A) is partially open with respect to the catalytic conformation, the other ( B) represents the most open conformation of PKA reported so far. In monomer A, the BIM2 inhibitor binds tightly via an induced fit in the ATP pocket. The indole moieties are rotated out of the plane with respect to the chemically related but planar inhibitor staurosporine. In molecule B a different conformer of BIM2 binds in a reversed orientation relative to the equivalent maleimide atoms in molecule A. Also, a critical active site salt bridge is disrupted, usually indicating the induction of an inactive conformation. Molecular modeling of the clinical phase III PKC inhibitor LY333531 into the electron density of BIM2 reveals the probable binding mechanism and explains selectivity properties of the inhibitor
    Type of Publication: Journal article published
    PubMed ID: 14996846
    Signatur Availability
    BibTip Others were also interested in ...
  • 4
    Keywords: PEPTIDE ; GROWTH-FACTOR ; Germany ; KINASE ; PATHWAY ; PATHWAYS ; SITE ; PROTEIN ; TRANSDUCTION ; LIGAND ; MECHANISM ; FAMILY ; PHOSPHORYLATION ; protein kinase ; PROTEIN-KINASE ; signal transduction ; SIGNAL ; CATALYTIC SUBUNIT ; ARRANGEMENT ; ESCHERICHIA-COLI ; SIGNAL-TRANSDUCTION ; MODULATION ; ATP ; PKA ; PLASMA-MEMBRANE ; Jun ; PROJECT ; FLEXIBILITY ; max ; STATES ; signaling ; STANDARD ; ABSENCE ; VARIANT ; CRYSTAL-STRUCTURES ; DEAMIDATION ; DEPENDENCE ; DEPENDENT PROTEIN-KINASE
    Abstract: Protein kinases comprise the major enzyme family critically involved in signal transduction pathways; posttranslational modifications affect their regulation and determine signaling states. The prototype protein kinase A (PKA) possesses an N-terminal alpha-helix (Helix A) that is atypical for kinases and is thus a major distinguishing feature of PKA. Its physiological function may involve myristoylation at the N-terminus and modulation via phosphorylation at serine 10. Here we describe an unusual structure of an unmyristoylated PKA, unphosphorylated at serine 10, with a completely ordered N-terminus. Using standard conditions (e.g., PKI 5-24, ATP site ligand, MEGA-8), a novel 2-fold phosphorylated PKA variant showed the ordered N-terminus in a new crystal packing arrangement. Thus, the critical factor for structuring the N-terminus is apparently the absence of phosphorylation of Ser10. The flexibility of the N-terminus, its myristoylation, and the conformational dependence on the phosphorylation state are consistent with a functional role for myristoylation
    Type of Publication: Journal article published
    PubMed ID: 15196017
    Signatur Availability
    BibTip Others were also interested in ...
  • 5
    Keywords: PEPTIDE ; CANCER ; INHIBITOR ; Germany ; INHIBITION ; KINASE ; INFORMATION ; SITE ; ENZYMES ; PROTEIN ; MOLECULES ; COMPLEX ; BINDING ; PHOSPHORYLATION ; protein kinase ; PROTEIN-KINASE ; MOLECULE ; TARGET ; CATALYTIC SUBUNIT ; DESIGN ; crystal structure ; CRYSTAL-STRUCTURE ; PKA ; RHO-ASSOCIATED KINASE ; TARGETS ; mutagenesis ; INSIGHTS ; INHIBITORS ; DEPENDENT PROTEIN-KINASE ; inhibitor selectivity ; protein kinase C inhibitor ; PUTATIVE TARGET ; rho-kinase inhibitor ; SERINE-THREONINE KINASE ; surrogate kinase
    Abstract: The AGC group of protein kinases comprises several targets for small molecule inhibitors of therapeutic significance. Crystal structure data facilitate the design or improvement of selective inhibitory molecules. Cross-selectivity of kinase inhibitors is often observed among closely related enzymes. Usually an obstacle for inhibitor design, cross-selectivity can be useful to obtain structural data from a related kinase, if not available from the original target. Protein kinase A (PKA), a representative of the AGC kinase group, has been cocrystallized with AGC group inhibitors from diverse chemical groups, thus providing structural information about binding modes, selectivity, and cross-selectivity. "Ersatz" kinases were created by mutating the inhibitor binding site of PKA to resemble other related kinases from the AGC group. The cocrystallization of these ersatz kinases with certain AGC group small molecule inhibitors elucidated some aspects of protein kinase inhibitor selectivity in this group of kinases
    Type of Publication: Journal article published
    PubMed ID: 15206489
    Signatur Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...