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{{Sandbox_Reserved_Robert_B_Rose_1}}
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=Cyclin-Dependent Kinase 3=
=Cyclin-Dependent Kinase 3=
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Cyclin-dependent kinase (Cdk) is a protein kinase family involved in regulation of the cell cycle. These Cdks are relatively small protein enzymes are responsible for mitosis, specifically transcriptional activity. They help activate DNA repair by being inhibited through phosphorylation during DNA damage response (DDR). They are also generally inactive during checkpoints along the cell cycle <ref name="overall cdk">PMID: 19995934</ref>. More than one Cdk can be in charge of different phases of the cell cycle. Often times, DDR is controlled by overall level of Cdk activity, and not by individual Cdks.  
Cyclin-dependent kinase (Cdk) is a protein kinase family involved in regulation of the cell cycle. These Cdks are relatively small protein enzymes are responsible for mitosis, specifically transcriptional activity. They help activate DNA repair by being inhibited through phosphorylation during DNA damage response (DDR). They are also generally inactive during checkpoints along the cell cycle. More than one Cdk can be in charge of different phases of the cell cycle. Often times, DDR is controlled by overall level of Cdk activity, and not by individual Cdks <ref name="overall cdk">PMID: 19995934</ref>.  
   
   
CDKs are activated through physical association with cyclin, a family of proteins, in which their abundance and proteolysis pattern within the cell vary according to the stage of cell cycle. Major transitions in the cell cycle are caused by activation of CDKs 1-4, which causes phosphorylation and dephosphorylation of key residues. Cells enter mitosis as protein-bound phosphates increase (Hames et al., 1998). In mammalian cells, it had been suggested that CDK-3, along with CDK-2, are required for G1/S stage (Hutchison p.111). Compared to CDK-1, 2, and 4, the role of CDK-3 is still unclear, as no cyclin partner had been found for it.  However, it had been shown that it delays cells in the G1 phase (Hutchison, p.149).  
CDKs are activated through physical association with cyclin, a family of proteins, in which their abundance and proteolysis pattern within the cell vary according to the stage of cell cycle. Major transitions in the cell cycle are caused by activation of CDKs 1-4, which causes phosphorylation and dephosphorylation of key residues. Cells enter mitosis as protein-bound phosphates increase (Hames et al., 1998). In mammalian cells, it had been suggested that CDK-3, along with CDK-2, are required for G1/S stage (Hutchison p.111). Compared to CDK-1, 2, and 4, the role of CDK-3 is still unclear, as no cyclin partner had been found for it.  However, it had been shown that it delays cells in the G1 phase (Hutchison, p.149).  


[[Image:cell_cycle_3.jpg]]
[[Image:cell_cycle_3.jpg]] <ref>http://scientopia.org/blogs/scicurious/2010/05/31/cell-cycle-p21-depression-and-neurogenesis-and-in-the-hippocampus/</ref>


Cdk’s are found in Eukaryotes, including human and yeast cells. Each organism has a different number of Cdks. In yeast, there is less, and more in humans. It is easier to study which Cdk is responsible for which part of the cell cycle in yeast than in humans, because of the level of complexity of Cdk and other cell activities in Homo Sapiens (Cerqueira et al., 2009). However, the function of Cdk is similar in all organisms in that it is part of the cell cycle regulation. For this reason, Cdk is often studied as targets for cancer treatment.
Cdk’s are found in Eukaryotes, including human and yeast cells. Each organism has a different number of Cdks. In yeast, there is less, and more in humans. It is easier to study which Cdk is responsible for which part of the cell cycle in yeast than in humans, because of the level of complexity of Cdk and other cell activities in Homo Sapiens <ref name="overall cdk">. However, the function of Cdk is similar in all organisms in that it is part of the cell cycle regulation. For this reason, Cdk is often studied as targets for cancer treatment.




<Structure load='1lfn' size='500' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />
<Structure load='1lfn' size='500' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' />


==OVERALL STRUCTURE==
==OVERALL STRUCTURE==
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Currently, no crystal structure for human CDK-3 had been resolved. There is only a theoretical molecular model available, based on analysis of 39 binary complexes of CDK-3:inhibitors. Data showed that 74.18% of CDK-3 structure is sequentially identical with CDK-2, thus making CDK-2 a perfect template model for CDK-3 protein. The Parmodel web server was used for comparative modeling and evaluation of protein structure, and molecular dynamics (5 ns) simulation was done with GROMACS <ref name="model">PMID: 19152876</ref>.
Currently, no crystal structure for human CDK-3 had been resolved. There is only a theoretical molecular model available, based on analysis of 39 binary complexes of CDK-3:inhibitors. Data showed that 74.18% of CDK-3 structure is sequentially identical with CDK-2, thus making CDK-2 a perfect template model for CDK-3 protein. The Parmodel web server was used for comparative modeling and evaluation of protein structure, and molecular dynamics (5 ns) simulation was done with GROMACS <ref name="model">PMID: 19152876</ref>.


Based on the molecular model, the overall structure of human CDK-3 was found to contain 305 amino acid residues, with a total molecular weight of 35,045.74 Da, and a theoretical pI of 8.86. Many features of secondary structure and molecular fork was found to very much resemble CDK-2 <ref name="model" />.
Based on the molecular model, the overall structure of human CDK-3 was found to contain 305 amino acid residues, with a total molecular weight of 35,045.74 Da, and a theoretical pI of 8.86. Many features of secondary structure and molecular fork was found to very much resemble CDK-2 <ref name="model">.


<scene name='Sandbox_Reserved_467/Secondary_structures/1'>Secondary structures</scene>
<scene name='Sandbox_Reserved_467/Secondary_structures/1'>Secondary structures</scene>


Human CDK-3 proteins was found to have alpha and beta structures. Its fold contains two alpha and two beta domains, with a larger C-terminal that is mostly alpha helical (this is characteristic of a typical protein kinase fold). CDK-3 is found to be folded into a bilobal structure, with smaller N-terminal lobe that is mostly β-sheet structure <ref name="model" />.  
Human CDK-3 proteins was found to have alpha and beta structures. Its fold contains two alpha and two beta domains, with a larger C-terminal that is mostly alpha helical (this is characteristic of a typical protein kinase fold). CDK-3 is found to be folded into a bilobal structure, with smaller N-terminal lobe that is mostly β-sheet structure <ref name="model">.  


The N-terminal lobe is found in a sheet of 5 antiparallel β-strands (β1-β5), and in one, large alpha helix (α-1). The C-terminal domain contains pseudo-4-helical bundle (α-2 to α-3, α-6), small β-ribbon (β-6 to β-8), and 2 alpha helices (α-5, α-7) <ref name="model" />.  
The N-terminal lobe is found in a sheet of 5 antiparallel β-strands (β1-β5), and in one, large alpha helix (α-1). The C-terminal domain contains pseudo-4-helical bundle (α-2 to α-3, α-6), small β-ribbon (β-6 to β-8), and 2 alpha helices (α-5, α-7) <ref name="model">.  


The ATP binding pocket is found in the cleft in between the bilobal structure. Most residues found in the ATP binding pocket is hydrophobic. The hydrophobic pocket can fit in different geometries of residues, like adenine derivatives and flavonoids <ref name="model" />.
The ATP binding pocket is found in the cleft in between the bilobal structure. Most residues found in the ATP binding pocket is hydrophobic. The hydrophobic pocket can fit in different geometries of residues, like adenine derivatives and flavonoids <ref name="model">.


==BINDING==
==BINDING==

Latest revision as of 01:47, 2 May 2012

This Sandbox is Reserved from 13/03/2012, through 01/06/2012 for use in the course "Proteins and Molecular Mechanisms" taught by Robert B. Rose at the North Carolina State University, Raleigh, NC USA. This reservation includes Sandbox Reserved 451 through Sandbox Reserved 500.
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Cyclin-Dependent Kinase 3Cyclin-Dependent Kinase 3

INTRODUCTIONINTRODUCTION

Cyclin-dependent kinase (Cdk) is a protein kinase family involved in regulation of the cell cycle. These Cdks are relatively small protein enzymes are responsible for mitosis, specifically transcriptional activity. They help activate DNA repair by being inhibited through phosphorylation during DNA damage response (DDR). They are also generally inactive during checkpoints along the cell cycle. More than one Cdk can be in charge of different phases of the cell cycle. Often times, DDR is controlled by overall level of Cdk activity, and not by individual Cdks [1].

CDKs are activated through physical association with cyclin, a family of proteins, in which their abundance and proteolysis pattern within the cell vary according to the stage of cell cycle. Major transitions in the cell cycle are caused by activation of CDKs 1-4, which causes phosphorylation and dephosphorylation of key residues. Cells enter mitosis as protein-bound phosphates increase (Hames et al., 1998). In mammalian cells, it had been suggested that CDK-3, along with CDK-2, are required for G1/S stage (Hutchison p.111). Compared to CDK-1, 2, and 4, the role of CDK-3 is still unclear, as no cyclin partner had been found for it. However, it had been shown that it delays cells in the G1 phase (Hutchison, p.149).

[2]

Cdk’s are found in Eukaryotes, including human and yeast cells. Each organism has a different number of Cdks. In yeast, there is less, and more in humans. It is easier to study which Cdk is responsible for which part of the cell cycle in yeast than in humans, because of the level of complexity of Cdk and other cell activities in Homo Sapiens Cite error: Closing </ref> missing for <ref> tag.

Based on the molecular model, the overall structure of human CDK-3 was found to contain 305 amino acid residues, with a total molecular weight of 35,045.74 Da, and a theoretical pI of 8.86. Many features of secondary structure and molecular fork was found to very much resemble CDK-2 <ref name="model">.

Human CDK-3 proteins was found to have alpha and beta structures. Its fold contains two alpha and two beta domains, with a larger C-terminal that is mostly alpha helical (this is characteristic of a typical protein kinase fold). CDK-3 is found to be folded into a bilobal structure, with smaller N-terminal lobe that is mostly β-sheet structure <ref name="model">.

The N-terminal lobe is found in a sheet of 5 antiparallel β-strands (β1-β5), and in one, large alpha helix (α-1). The C-terminal domain contains pseudo-4-helical bundle (α-2 to α-3, α-6), small β-ribbon (β-6 to β-8), and 2 alpha helices (α-5, α-7) <ref name="model">.

The ATP binding pocket is found in the cleft in between the bilobal structure. Most residues found in the ATP binding pocket is hydrophobic. The hydrophobic pocket can fit in different geometries of residues, like adenine derivatives and flavonoids <ref name="model">.

BINDINGBINDING

Binding between CDK3 and inhibitors at the molecular fork require intermolecular hydrogen bonds. They are responsible for specificity and affinity between the protein and its ligand. A common pattern of this is shared with CDK2. At the molecular fork, or where inhibitors and ATP can bind, it is determined so far that an acceptor close to N-H in Leu83 and 1 H-bond donor close to C=O in Glu81 and/or Leu83 are present [3].

Although specific contact areas are not yet concluded, a high correlation coefficient between CDK-3 and CDK-2 pkd values suggest that CDK-2 inhibitors can also inhibit CDK-3. Pkd values for various known CDK-2 inhibitors with were analyzed in its interaction with CDK-3, and 4 inhibitors were shown to be the best[3]:

- n-methyl-{4-[2-(7-oxo-6, 7-dihydro-8h-[1,3]thiazolo[5,4-e] indol-8-ylidene) hydrazine]phenyl}methanesulfonamide [3]

- (2r)-1-(dimethylamino)-3-{4-[6-{[2-fluoro-5-(trifluoromethyl)phenyl] amino}pyrimidin-4-yl)amino]phenoxy}propan-2-ol [3]

- (5-chloropyrazolo[1,5-a]pyrimidin-7-yl)-(4-methanesulfonylphenyl)amine [3]

- din-232306 6-(3,4-dihydroxybenzyl)-3-ethyl-1-(2,4,6-trichlorophenyl-1h-pyrazolo[3,4-d]pyrimidin-4(5h)-one[3]

MOLECULAR DYNAMICSMOLECULAR DYNAMICS

Molecular dynamics of human CDK-3 protein model was assessed by RMSF values. Backbone fluctuations, or residues of higher flexibility, occur in loop and turn regions of residues that surround the alpha-beta-alpha fold. Relatively high RMSF values are found in more flexible regions in the CDK-3 structure. These regions are: L1 (turn composed of Glu25- Gly27), L2 (loop Leu37- Pro45), L3 (turn Glu73- Arg74), L4 (loop Thr94- Pro100), L5 (turn Tyr159- His161), and L6 (loop Gly220- Gly247) [3].

MEDICAL IMPLICATIONMEDICAL IMPLICATION

REFERENCESREFERENCES

Perez, Patricia C., Rafael A. Cacerez, Fernanda Canduri, and Walter F. Azevedo. "Molecular Modeling and Dynamics Simulation of Human Cyclin-dependent Kinase 3 Complexed with Inhibitors." Computers in Biology and Medicine 39(2008): 130-140. PubMed. Web. 1 May 2012. PMID: 19152876 doi:10.1016/j.compbiomed.2008.11.004


FOOTNOTESFOOTNOTES

  1. ↑ Cerqueira A, Santamaria D, Martinez-Pastor B, Cuadrado M, Fernandez-Capetillo O, Barbacid M. Overall Cdk activity modulates the DNA damage response in mammalian cells. J Cell Biol. 2009 Dec 14;187(6):773-80. Epub . PMID:19995934 doi:10.1083/jcb.200903033
  2. ↑ http://scientopia.org/blogs/scicurious/2010/05/31/cell-cycle-p21-depression-and-neurogenesis-and-in-the-hippocampus/
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Cite error: Invalid <ref> tag; no text was provided for refs named model

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