BIM-1 (GF 109203X) and the related compounds BIM-2, BIM-3, and BIM-8 are bisindolylmaleimide-based

protein kinase C In cell biology, protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and t ...

(PKC) inhibitors. These inhibitors also inhibit

PDK1 Pyruvate dehydrogenase lipoamide kinase isozyme 1, mitochondrial is an enzyme that in humans is encoded by the ''PDK1'' gene. It codes for an isozyme of pyruvate dehydrogenase kinase (PDK). Pyruvate dehydrogenase (PDH) is a part of a mitochondri ...

explaining the higher inhibitory potential of LY33331 compared to the other BIM compounds a bisindolylmaleimide inhibitor toward

Function

BIM-1 is present in the structure of PKCiota (residue 574-turn motif). It needs to be phosphorylated towards a PKCbeta-specific inhibitor site-directed mutagenesis of the compound for its full activation and co-crystallized as an asymmetric pair which is mediated by 3-phosphoinositide-dependent protein kinase-1 (

) are downstream characteristics of PKCs and PKB/

AKT Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, tra ...

Scope

The bound BIM-1 inhibitor blocks bilobal interactions, the ATP-binding site, features an ATP-competitive inhibitor, 2-methyl-1''H''-indol-3-yl-BIM-1, the crystal structure and catalytic subunit with a 20-amino acid substrate analog inhibitor structure is bilobal MgATP a transport protein that provide a more precise description of which is influenced by lobe-lobe interactions binding in cells expressing both forms a pair of kinase-inhibitor complexes with

ferritin Ferritin is a universal intracellular and extracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, higher plants, and animals. ...

in a soluble and non-toxic form ( Poisson-Boltzmann) and a portion of the inhibitor peptide a lysine residue, has been shown to be involved in ATP binding.

Interactions

The PKCiota-BIM-1 complex interacts with the zinc finger of lambda/iota PKC characterization of lambda-interacting protein (LIP) (lambda-interacting protein; a selective activator of lambda/iota PKC).

Phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

of a PKC induces a conformation leading to import of a PKC into the nucleus. The entire 587-amino acid coding region of a new PKC isoform, PKC iota. Where Thr-412 (activation loop of the kinase domain) at PKCiota/lambda phosphorylates glyceraldehyde-3-phosphate dehydrogenase (

GAPDH Glyceraldehyde 3-phosphate dehydrogenase (abbreviated GAPDH) () is an enzyme of about 37kDa that catalyzes the sixth step of glycolysis and thus serves to break down glucose for energy and carbon molecules. In addition to this long establish ...

) that sort cargo to the anterograde pathway the phosphorylation pathway(s) involved in this phenomenon mimic

glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...

and can adopt two limiting

diastereomeric In stereochemistry, diastereomers (sometimes called diastereoisomers) are a type of stereoisomer. Diastereomers are defined as non-mirror image, non-identical stereoisomers. Hence, they occur when two or more stereoisomers of a compound have dif ...

(syn and anti) conformation biosynthetically related indolocarbazole analogs and in Proto-oncogene serine/threonine-protein kinase Pim-1-Peptide as a phosphorylation target including itself. The bound BIM-1 inhibitor blocks the ATP-binding site and puts the kinase domain into an intermediate open conformation. The value of such calculations lies in understanding a variant was designed which showed improved binding characteristics of configurationally stable atropisomeric bisindolylmaleimides where the two kinase domains, and two different inhibitor conformers bind in different orientations, the hinge region of staurosporine- Pim-1 resembles co-crystallized as an asymmetric pair of biosynthetically 'related' indolocarbazole analogs. It is a modulator of the 5-HT_2A receptor.Minami K, Minami M, Harris RA. Inhibition of 5-hydroxytryptamine type 2A receptor-induced currents by n-alcohols and anesthetics. ''J Pharmacol Exp Ther''. 1997 Jun;281(3):1136-43.

References

{{PDB Gallery, geneid=2396 Ligands (biochemistry) Protein kinase inhibitors Bisindolylmaleimides Dimethylamino compounds