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Introduction

This is a sample scene created with SAT to by Group, and another to make of the protein.

GSK-3 is a serine/threonine protein kinase which regulates the addition of phosphate molecules onto serineand threonine amino acid residues. Serine/threonine protein kinases are responsible for phosphorylating the serine/threonine kinase receptors which play a role in the regulation of cell proliferation, programmed cell death (apoptosis), cell differentiation, and embryonic development ^[1]. GSK-3 has two isoforms, GSK-3 beta and GSK-3 alpha. GSK-3 beta is more involved in energy metabolism, neuronal cell development, and body pattern formation, while GSK-3 alpha has more function with WNT signaling pathways. GSK-3 beta is found in most mammals, all with similar structure and function. In experiments when GSK-3 beta was perturbed in mice, embryonic lethality during mid-gestation was demonstrated.

GSK-3 beta has been shown to negatively regulates TGF-beta1 and Angiotensin II-mediated cellular activity through interaction with Smad3. GSK-3 beta directly interacts with Smad3, preventing its movement into the nucleolus, which don't allow it to perform cell death. This forces Angiotensin II apoptosis in cardiac myocytes^[2]. Other enzymes that this kinase interacts with are: AKAP11, AXIN1, AXIN2, AR, CTNNB1, DNM1L, MACF1 MUC1, SMAD3[ NOTCH1,NOTCH2, P53, PRKAR2A, SGK3, and TSC2^[3]. Recent research in regards to GSK-3 includes type II diabetes , Alzheimer's Disease, inflammation, cancer, and bipolar disorder. This page demonstrates a GSK-3 complex with a Staurosporine inhibitor.

Overall Structure

Glycogen Synthase Kinase-3 (GSK-3) is a serine/threonine kinase monomer and has an overall structure that is characteristic of the apoenzyme. It has two phosphorylation sites that are involved in catalysis. One of these sites is Ser9, which is the phosphorylation site for AKT, resulting in the inactivation of GSK-3beta. The second phosphorylation site is Tyr216, located on the activation loop (shown in green), and is responsible for the increase in catalytic activity. GSK-3beta has the characteristic two-domain kinase fold, containing a N-terminal beta-strand domain (light blue, residues 25-138) and a C-terminal alpha-helical domain (red, residues 139-343). There is an interface between the alpha and beta domains, at which the ATP-binding site is located, encircled by the hinge and the glycine-rich loop. The activation loop (purple) runs along the surface of the substrate-binding groove. There are 39 residues in the C-terminus end that are outside the main kinase fold. These residues form a small domain that closely packs next to the alpha-helical domain. The beta-strand domain is formed by seven beta-strands that run in an antiparallel formation. Strands 2-6 form a beta-barrel, through which a short alpha helix (yellow, residues 96-102) aligns against the beta-barrel. Two of this short helix’s residues play important roles in the catalytic action of GSK-3beta. A salt bridge, which is important in binding interactions, is positioned in the active site between Glu97 and Lys85^[4].

Binding Interactions

Additional Features

The GSK-3β and staurosporine complex shows . It is observed that there are direct H-bonds, water-mediated polar interactions and hydrophobic interactions in the GSK-3β and staurosporine complex. There are only two direct H-bonds, and they are observed between

• The carbonyl oxygen of Asp 133 and N¹ (nitrogen) of staurosporine. The length of this hydrogen bond is 2.93 Å.
• The backbone nitrogen of Val 135 and O⁵ (oxygen) of staurosporine. The length of this hydrogen bond is 2.76 Å.

Besides direct H-bond, the water-mediated polar interactions are observed between the carbonyl oxygen of Gln 185 and N⁴ (nitrogen) of the glycosidic ring. The typical hydrogen bond (H-bond) is categorized to be between 2.2 and 4.0 Å ^[5]. Since many pdb files lack hydrogen atoms, a significant H-bond can be considered when donor-acceptor distance are probably 3.5 Å^[5]