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From Proteopedia

Revision as of 16:22, 30 March 2015

'Protein kinase C related kinase/Tofacitinib (prostrate and ovarian cancer)-4OTI'

Introduction

Protein kinase C, an enzyme that is activated by the receptor-mediated hydrolysis of inositol phospholipids, relays information in the form of a variety of extracellular signals across the membrane to regulate many Ca2+-dependent processes. At an early phase of cellular responses, the enzyme appears to have a dual effect, providing positive forward as well as negative feedback controls over various steps of its own and other signaling pathways, such as the receptors that are coupled to inositol phospholipid hydrolysis and those of some growth factors. In biological systems, a positive signal is frequently followed by immediate negative feedback regulation. Such a novel role of this system seems to give a logical basis for clarifying the biochemical mechanism of signal transduction, and to add a new dimension essential to our understanding of cell-to-cell communication of the protein.

Overall Structure

Protein Kinase C is comprised of 15 Alpha helices and 8 beta strands. The beta sheets form a pocket for the ligand, leaving a portion exposed to interact with other molecules. Its beta sheets are arranged antiparallel giving added stability to the molecule, from hydrogen bonding oriented in a favorable manor. Protein Kinase C's ligand MI1 has a structural formula of C_16 H_20 N_6 O, and there are a total of 304 residues in the protein.

Protein Kinase C contains an N terminal region providing regulation, and a C terminal that proposes as a catalytic region. Each of these regions are approximately 20-40 kDa and 45kDa in size respectively. The N and C terminals are separated by a hinge region, which can easily be adjusted when the enzyme is bound to a membrane.

Binding Interactions

The function of Protein kinase C depends on three mechanisms: 1. 2. Cofactor binding 3. Interaction with targeting proteins

Protein kinase C has two domains: C1 and C2. C1: - Cys-rich region present in all protein kinase C molecules - typical and atypical C1 domains - binding of ligand does not result in any significant conformational changes but it does dramatically alter the surface properties C2: -Ca2+ dependent - typical and atypical C2 domains - 2 types which differ in the connectivity of the strands:

      1. Type 1 for domains that follow the C1 domain
      2. Type 2 for domains that lead the C1 domain

- multiple aspartic acid residues - module approaches membrane in a "jaws first" orientation

Additional Features

A characteristic feature of PRK1 is a C-terminal regulatory region (C-tail). This section of the protein regulates enzyme activity and can recruit binding partners^[1].The C-tail can be found at the base of the C-lobe and encircles the C-lobe. The C-tail residue Phe910 is projects into the enzyme active site and is stacked between the sidechains of Leu627 and Gly707. In addition to its main role in the cell, PRK1 also aids in the epigenetic regulation of transcription. A threonine residue, Thr11 phosphorylates histone H3 and can enhance transcription of the nearby genes.

PRK1 is inhibited by the naturally occurring molecule staurosporine. Clinical trials are being ran on several PRK1 inhibitors to observe their medical benefits. Even though PRK1 plays a role in pathways implicated by ovarian and prostate cancer, these inhibitors are being evaluated for treating other diseases. Lestaurtinib (CEP701) is a staurosporine analogue and inhibits several other protein kinases.CEP701 is being evaluated as a potential treatment for myelofibrosis and AML. CEP701 causes a substantial disordering of the C-tail when it binds. Another drug, tofacitinib, has been approved for use as a rheumatoid arthritis treatment. Tofacitinib does not show the same displacement when it binds, but does make van der Waals interactions with the sidechain of Phe910. Instead, it results in a clashing with the sidechain of the G-loop residue Phe632 and causes it to position away from the ATP binding site.

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Quiz Question 1

What effect do would you expect a decrease in pH to have on 4oti's binding?

Quiz Question 2

What types of amino acids must an inhibitor be able to bind to in order to successfully inhibit PRK1?
a. Aromatic amino acids (Phe, Tyr, Trp)
b. Hydrophobic amino acids (Ala, Phe, Val)
c. Hydrophilic amino acids (Ser, Thr, Tyr)
d. Both A and B
e. Both A and C

See Also

• Protein_kinase_C

• Androgen_receptor

• Histone

• Histone_deacetylase

• 4otd

• 4oth

• 4otg

Credits

Introduction - Md Shafiul Hossain

Overall Structure - name of team member

Drug Binding Site - name of team member

Additional Features - name of team member

Quiz Question 1 - name of team member

Quiz Question 2 - name of team member

References

1. ↑ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1783090/