Sandbox Reserved 1491

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- <scene name='80/802665/Cl/1'>Cl-</scene> : one binding site, only in chain A.
- <scene name='80/802665/Cl/1'>Cl-</scene> : one binding site, only in chain A.
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2xml presents, in each of the two chains, parallel [https://en.wikipedia.org/wiki/Beta_sheet β sheets] around <scene name='80/802665/Oga_pocket/1'>OGA</scene>, forming an '''hydrophobic pocket''' (mainly made of aromatic acid). OGA interacts with 2xml amino acids through hydrogen bonds and coordination bonds with Ni2+.
2xml presents, in each of the two chains, parallel [https://en.wikipedia.org/wiki/Beta_sheet β sheets] around <scene name='80/802665/Oga_pocket/1'>OGA</scene>, forming an '''hydrophobic pocket''' (mainly made of aromatic acid). OGA interacts with 2xml amino acids through hydrogen bonds and coordination bonds with Ni2+.
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== Epigenetics ==
== Epigenetics ==
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Specific enzymes are directly involved in the '''modification of genes expression''' without altering the nucleotide sequence. They can modify the chromatin structure by '''adding''' (writers), '''reading''' (readers) or '''removing''' (erasers) marks : acetyl, methyl, phosphoryl groups, ubiquitin<ref>Kupershmit, Ilana, Hanan Khoury-Haddad, Samah W. Awwad, Noga Guttmann-Raviv, and Nabieh Ayoub. “KDM4C (GASC1) Lysine Demethylase Is Associated with Mitotic Chromatin and Regulates Chromosome Segregation during Mitosis.” Nucleic Acids Research 42, no. 10 (June 2, 2014): 6168–82. https://doi.org/10.1093/nar/gku253.</ref>... These [https://en.wikipedia.org/wiki/Epigenetics epigenetic]marks can either make the gene sequence more or less accessible depending on their nature, histones and labelled amino acids. All combinations of the nature and the localization of the marks form the histone code.
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Specific enzymes are directly involved in the '''modification of genes expression''' without altering the nucleotide sequence. They can modify the chromatin structure by '''adding''' (writers), '''reading''' (readers) or '''removing''' (erasers) marks : acetyl, methyl, phosphoryl groups, ubiquitin<ref>Kupershmit, Ilana, Hanan Khoury-Haddad, Samah W. Awwad, Noga Guttmann-Raviv, and Nabieh Ayoub. “KDM4C (GASC1) Lysine Demethylase Is Associated with Mitotic Chromatin and Regulates Chromosome Segregation during Mitosis.” Nucleic Acids Research 42, no. 10 (June 2, 2014): 6168–82. https://doi.org/10.1093/nar/gku253.</ref>... These [https://en.wikipedia.org/wiki/Epigenetics epigenetic]marks can either make the gene sequence more or less accessible for [https://en.wikipedia.org/wiki/Transcription_factor transcription factors] depending on their nature, histones and labelled amino acids. All combinations of the nature and the localization of the marks form the [https://en.wikipedia.org/wiki/Histone_code histone code].
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KDM4C is a histone demethylase. This newly discovered class of proteins plays a central role in the '''epigenetic modifications''' : it removes the methyl group (which is very stable) from the epigenetically modified amino acid. Its actions has directed consequences on gene expression. By removing the third methyl group from '''Lysine 9 of histone 3''' (H3K9me3), KDM4C promotes the formation of euchromatin and therefore '''transcriptional activation'''. However, KDM4C indirectly condenses chromatin by removing the third methyl group from '''Lysine 36 of histone 3''' (H3K36me3), leading to a '''repression of target genes expression'''<ref>Berry, W. L., and R. Janknecht. “KDM4/JMJD2 Histone Demethylases: Epigenetic Regulators in Cancer Cells.” Cancer Research 73, no. 10 (May 15, 2013): 2936–42.</ref>.
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KDM4C is a histone demethylase. This newly discovered class of proteins plays a central role in the histone modifications : it removes the methyl group (which is very stable) from the epigenetically modified amino acid. Its actions has directed consequences on gene expression. By removing repressive histone marks (H3K9me3 and H3K36me3) from target genes KDM4C promotes the formation of euchromatin and therefore transcriptional activation.
 
== Disease ==
== Disease ==
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- Ability to invade the body and other organs. <ref>Douglas Hanahan et Robert A. Weinberg, « The hallmarks of cancer », Cell, vol. 100,‎ 7 janvier 2000, p. 57-70 (PMID 10647931)</ref>
- Ability to invade the body and other organs. <ref>Douglas Hanahan et Robert A. Weinberg, « The hallmarks of cancer », Cell, vol. 100,‎ 7 janvier 2000, p. 57-70 (PMID 10647931)</ref>
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The development of cancer begins with the modification of the sequence and expression of the genes involved in the [https://en.wikipedia.org/wiki/Cell_cycle cell cycle]. <ref>https://en.wikipedia.org/wiki/Cancer</ref>
The development of cancer begins with the modification of the sequence and expression of the genes involved in the [https://en.wikipedia.org/wiki/Cell_cycle cell cycle]. <ref>https://en.wikipedia.org/wiki/Cancer</ref>
The transformation from healthy cells to cancer cells is carried out in two stages: '''carcinogenesis and tumorigenesis'''.
The transformation from healthy cells to cancer cells is carried out in two stages: '''carcinogenesis and tumorigenesis'''.
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During [https://en.wikipedia.org/wiki/Carcinogenesis carcinogenesis], cells accumulate '''genetic abnormalities''', particularly in [https://en.wikipedia.org/wiki/Oncogene oncogenic] sequences. '''Oncogenes''' are positive regulators of cell proliferation. After a mutation, they become hyperactive and cause an excessive cellular growth. [https://en.wikipedia.org/wiki/Caretaker_gene '''Gatekeeper genes'''] (genes that allow the passage from one stage of the cell cycle to the next) can also be mutated, leading to uncontrolled cell proliferation.
During [https://en.wikipedia.org/wiki/Carcinogenesis carcinogenesis], cells accumulate '''genetic abnormalities''', particularly in [https://en.wikipedia.org/wiki/Oncogene oncogenic] sequences. '''Oncogenes''' are positive regulators of cell proliferation. After a mutation, they become hyperactive and cause an excessive cellular growth. [https://en.wikipedia.org/wiki/Caretaker_gene '''Gatekeeper genes'''] (genes that allow the passage from one stage of the cell cycle to the next) can also be mutated, leading to uncontrolled cell proliferation.
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During tumorigenesis, cancer becomes invasive: cancer cells invade other healthy organs.
During tumorigenesis, cancer becomes invasive: cancer cells invade other healthy organs.
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KDM4C is involved in carcinogenesis as an oncogene. Indeed, by catalyzing the demethylation of H3K9-me3 (lysine 9 from trimethylated histones 3) to H3K9-me2 (lysine 9 from dimethylated histones 3), this protein increases the expression of its target genes. Several KDM4C target genes are involved in [https://en.wikipedia.org/wiki/Cell_growth cell growth]. For example, they influence mitogenic signalling - which promotes mitosis and cell division -, cell cycle regulation and translation.
KDM4C is involved in carcinogenesis as an oncogene. Indeed, by catalyzing the demethylation of H3K9-me3 (lysine 9 from trimethylated histones 3) to H3K9-me2 (lysine 9 from dimethylated histones 3), this protein increases the expression of its target genes. Several KDM4C target genes are involved in [https://en.wikipedia.org/wiki/Cell_growth cell growth]. For example, they influence mitogenic signalling - which promotes mitosis and cell division -, cell cycle regulation and translation.
In cancer cells, KDM4C expression is enhanced. Thus, the growth of tumor cells is greatly increased. <ref>Gregory, Brittany L., and Vivian G. Cheung. ‘Natural Variation in the Histone Demethylase, KDM4C, Influences Expression Levels of Specific Genes Including Those That Affect Cell Growth’. Genome Research 24, no. 1 (January 2014): 52–63. https://doi.org/10.1101/gr.156141.113</ref>
In cancer cells, KDM4C expression is enhanced. Thus, the growth of tumor cells is greatly increased. <ref>Gregory, Brittany L., and Vivian G. Cheung. ‘Natural Variation in the Histone Demethylase, KDM4C, Influences Expression Levels of Specific Genes Including Those That Affect Cell Growth’. Genome Research 24, no. 1 (January 2014): 52–63. https://doi.org/10.1101/gr.156141.113</ref>
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In addition, KDM4C is involved in the correct [https://en.wikipedia.org/wiki/Chromosome_segregation segregation of chromosomes]. Its high presence in tumor cells therefore ensures their viability.<ref>Garcia, Jeison, and Fernando Lizcano. ‘KDM4C Activity Modulates Cell Proliferation and Chromosome Segregation in Triple-Negative Breast Cancer’. Breast Cancer : Basic and Clinical Research 10 (2 November 2016): 169–75. https://doi.org/10.4137/BCBCR.S40182.</ref>
In addition, KDM4C is involved in the correct [https://en.wikipedia.org/wiki/Chromosome_segregation segregation of chromosomes]. Its high presence in tumor cells therefore ensures their viability.<ref>Garcia, Jeison, and Fernando Lizcano. ‘KDM4C Activity Modulates Cell Proliferation and Chromosome Segregation in Triple-Negative Breast Cancer’. Breast Cancer : Basic and Clinical Research 10 (2 November 2016): 169–75. https://doi.org/10.4137/BCBCR.S40182.</ref>
Finally, KDM4C also plays a role in the tumorigenesis of certain cancers, such as '''breast cancer''', since it allows the proliferation of cancer cells, their migration and their invasive capacity in the triple-negative breast cancer.
Finally, KDM4C also plays a role in the tumorigenesis of certain cancers, such as '''breast cancer''', since it allows the proliferation of cancer cells, their migration and their invasive capacity in the triple-negative breast cancer.
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For all the implications of KDM4C in different cancers, it is one of the main '''targets of anti-cancer treatments'''.
For all the implications of KDM4C in different cancers, it is one of the main '''targets of anti-cancer treatments'''.
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This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.
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</StructureSection>
</StructureSection>
== References ==
== References ==
<references/>
<references/>

Revision as of 16:56, 10 January 2019

This Sandbox is Reserved from 06/12/2018, through 30/06/2019 for use in the course "Structural Biology" taught by Bruno Kieffer at the University of Strasbourg, ESBS. This reservation includes Sandbox Reserved 1480 through Sandbox Reserved 1543.
To get started:
  • Click the edit this page tab at the top. Save the page after each step, then edit it again.
  • Click the 3D button (when editing, above the wikitext box) to insert Jmol.
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More help: Help:Editing

2xml - KDM4C catalytic domain

2xml is a 2 chain structure. This domain belongs to the Human KDM4C protein.

KDM4C is a histone demethylase involved in the specific demethylation of trimethylated residues (Lys 9 and Lys 36 of histone 3). These marks are specific tags for genes expression modification. KDM4C plays a main role in the modification of cell cycle genes expression and thus involved in the growth of tumoral cells.

Structure of 2xml - monomeric domain of KDM4C

Drag the structure with the mouse to rotate

References

  1. ↑ Tamaru, H. “Confining Euchromatin/Heterochromatin Territory: Jumonji Crosses the Line.” Genes & Development 24, no. 14 (July 15, 2010): 1465–78. https://doi.org/10.1101/gad.1941010.
  2. ↑ Nasir Javaid, and Sangdun Choi. “Acetylation- and Methylation-Related Epigenetic Proteins in the Context of Their Targets.” Genes 8, no. 8 (August 7, 2017): 196. https://doi.org/10.3390/genes8080196
  3. ↑ Shi, Y. G., and Y.-i. Tsukada. “The Discovery of Histone Demethylases.” Cold Spring Harbor Perspectives in Biology 5, no. 9 (September 1, 2013): a017947–a017947. https://doi.org/10.1101/cshperspect.a017947.
  4. ↑ Labbé, Roselyne M., Andreana Holowatyj, and Zeng-Quan Yang. “Histone Lysine Demethylase (KDM) Subfamily 4: Structures, Functions and Therapeutic Potential.” American Journal of Translational Research 6, no. 1 (2013): 1–15
  5. ↑ Leurs, Ulrike, Brian Lohse, Kasper D. Rand, Shonoi Ming, Erik S. Riise, Philip A. Cole, Jesper L. Kristensen, and Rasmus P. Clausen. “Substrate- and Cofactor-Independent Inhibition of Histone Demethylase KDM4C.” ACS Chemical Biology 9, no. 9 (September 19, 2014): 2131–38. https://doi.org/10.1021/cb500374f.
  6. ↑ http://consurf.tau.ac.il/fgij/fg.htm?mol=/temp/2XMLA_ConSurf_DB_pipe.pdb
  7. ↑ Kupershmit, Ilana, Hanan Khoury-Haddad, Samah W. Awwad, Noga Guttmann-Raviv, and Nabieh Ayoub. “KDM4C (GASC1) Lysine Demethylase Is Associated with Mitotic Chromatin and Regulates Chromosome Segregation during Mitosis.” Nucleic Acids Research 42, no. 10 (June 2, 2014): 6168–82. https://doi.org/10.1093/nar/gku253.
  8. ↑ Berry, W. L., and R. Janknecht. “KDM4/JMJD2 Histone Demethylases: Epigenetic Regulators in Cancer Cells.” Cancer Research 73, no. 10 (May 15, 2013): 2936–42.
  9. ↑ Douglas Hanahan et Robert A. Weinberg, « The hallmarks of cancer », Cell, vol. 100,‎ 7 janvier 2000, p. 57-70 (PMID 10647931)
  10. ↑ https://en.wikipedia.org/wiki/Cancer
  11. ↑ Gregory, Brittany L., and Vivian G. Cheung. ‘Natural Variation in the Histone Demethylase, KDM4C, Influences Expression Levels of Specific Genes Including Those That Affect Cell Growth’. Genome Research 24, no. 1 (January 2014): 52–63. https://doi.org/10.1101/gr.156141.113
  12. ↑ Garcia, Jeison, and Fernando Lizcano. ‘KDM4C Activity Modulates Cell Proliferation and Chromosome Segregation in Triple-Negative Breast Cancer’. Breast Cancer : Basic and Clinical Research 10 (2 November 2016): 169–75. https://doi.org/10.4137/BCBCR.S40182.
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