Jonathan O'Donnell sandbox 1 - Revision history

Jonathan O'Donnell sandbox 1 - Revision history http://52.214.119.220/wiki/index.php?title=Jonathan_O%27Donnell_sandbox_1&action=history Revision history for this page on the wiki en MediaWiki 1.11.2 Mon, 13 Apr 2026 23:09:04 GMT Ann Taylor at 16:09, 31 August 2009 http://52.214.119.220/wiki/index.php?title=Jonathan_O%27Donnell_sandbox_1&diff=990536&oldid=prev <p></p> <table style="background-color: white; color:black;"> <col class='diff-marker' /> <col class='diff-content' /> <col class='diff-marker' /> <col class='diff-content' /> <tr> <td colspan='2' style="background-color: white; color:black;">←Older revision</td> <td colspan='2' style="background-color: white; color:black;">Revision as of 16:09, 31 August 2009</td> </tr> <tr><td colspan="2" class="diff-lineno">Line 12:</td> <td colspan="2" class="diff-lineno">Line 12:</td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>The tumor suppressor protein p53 is mutated in more than 50% of invasive cancers. About 30% of the mutations are found in six major "hot spot" codons located in its DNA binding core domain. To gain structural insight into the deleterious effects of such mutations and their rescue by suppressor mutations, we determined the crystal structures of the p53 core domain incorporating the hot spot mutation <scene name='Ann_Taylor/<del style="color: red; font-weight: bold; text-decoration: none;">sandbox_1</del>/R249s/1'>R249S</scene>, the core domain incorporating R249S and a second-site suppressor mutation H168R (referred to as the double mutant R249S/H168R) and its sequence-specific complex with DNA and of the triple mutant R249S/H168R/T123A. The structural studies were accompanied by transactivation and apoptosis experiments. The crystal structures show that the region at the vicinity of the mutation site in the R249S mutant displays a range of conformations [wild-type (wt) and several mutant-type conformations] due to the loss of stabilizing interactions mediated by R249 in the wt protein. As a consequence, the protein surface that is critical to the formation of functional p53-DNA complexes, through protein-protein and protein-DNA interactions, is largely distorted in the mutant conformations, thus explaining the protein's "loss of function" as a transcription factor. The structure of this region is restored in both R249S/H168R and R249S/H168R/T123A and is further stabilized in the complex of R249S/H168R with DNA. Our functional data show that the introduction of H168R as a second-site suppressor mutation partially restores the transactivation capacity of the protein and that this effect is further amplified by the addition of a third-site mutation T123A. These findings together with previously reported data on wt and mutant p53 provide a structural framework for understanding p53 dysfunction as a result of oncogenic mutations and its rescue by suppressor mutations and for a potential drug design aimed at restoring wt activity to aberrant p53 proteins.</div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>The tumor suppressor protein p53 is mutated in more than 50% of invasive cancers. About 30% of the mutations are found in six major "hot spot" codons located in its DNA binding core domain. To gain structural insight into the deleterious effects of such mutations and their rescue by suppressor mutations, we determined the crystal structures of the p53 core domain incorporating the hot spot mutation <scene name='Ann_Taylor/<ins style="color: red; font-weight: bold; text-decoration: none;">Sandbox_1</ins>/R249s/1'>R249S</scene>, the core domain incorporating R249S and a second-site suppressor mutation H168R (referred to as the double mutant R249S/H168R) and its sequence-specific complex with DNA and of the triple mutant R249S/H168R/T123A. The structural studies were accompanied by transactivation and apoptosis experiments. The crystal structures show that the region at the vicinity of the mutation site in the R249S mutant displays a range of conformations [wild-type (wt) and several mutant-type conformations] due to the loss of stabilizing interactions mediated by R249 in the wt protein. As a consequence, the protein surface that is critical to the formation of functional p53-DNA complexes, through protein-protein and protein-DNA interactions, is largely distorted in the mutant conformations, thus explaining the protein's "loss of function" as a transcription factor. The structure of this region is restored in both R249S/H168R and R249S/H168R/T123A and is further stabilized in the complex of R249S/H168R with DNA. Our functional data show that the introduction of H168R as a second-site suppressor mutation partially restores the transactivation capacity of the protein and that this effect is further amplified by the addition of a third-site mutation T123A. These findings together with previously reported data on wt and mutant p53 provide a structural framework for understanding p53 dysfunction as a result of oncogenic mutations and its rescue by suppressor mutations and for a potential drug design aimed at restoring wt activity to aberrant p53 proteins.</div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Structural basis of restoring sequence-specific DNA binding and transactivation to mutant p53 by suppressor mutations., Suad O, Rozenberg H, Brosh R, Diskin-Posner Y, Kessler N, Shimon LJ, Frolow F, Liran A, Rotter V, Shakked Z, J Mol Biol. 2009 Jan 9;385(1):249-65. Epub 2008 Oct 30. PMID:18996393</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Structural basis of restoring sequence-specific DNA binding and transactivation to mutant p53 by suppressor mutations., Suad O, Rozenberg H, Brosh R, Diskin-Posner Y, Kessler N, Shimon LJ, Frolow F, Liran A, Rotter V, Shakked Z, J Mol Biol. 2009 Jan 9;385(1):249-65. Epub 2008 Oct 30. PMID:18996393</div></td></tr> </table> Mon, 31 Aug 2009 16:09:32 GMT Ann Taylor http://52.214.119.220/wiki/index.php/Talk:Jonathan_O%27Donnell_sandbox_1 Ann Taylor at 16:08, 31 August 2009 http://52.214.119.220/wiki/index.php?title=Jonathan_O%27Donnell_sandbox_1&diff=990535&oldid=prev <p></p> <table style="background-color: white; color:black;"> <col class='diff-marker' /> <col class='diff-content' /> <col class='diff-marker' /> <col class='diff-content' /> <tr> <td colspan='2' style="background-color: white; color:black;">←Older revision</td> <td colspan='2' style="background-color: white; color:black;">Revision as of 16:08, 31 August 2009</td> </tr> <tr><td colspan="2" class="diff-lineno">Line 12:</td> <td colspan="2" class="diff-lineno">Line 12:</td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>The tumor suppressor protein p53 is mutated in more than 50% of invasive cancers. About 30% of the mutations are found in six major "hot spot" codons located in its DNA binding core domain. To gain structural insight into the deleterious effects of such mutations and their rescue by suppressor mutations, we determined the crystal structures of the p53 core domain incorporating the hot spot mutation <scene name='<del style="color: red; font-weight: bold; text-decoration: none;">Jonathan_O'Donnell_sandbox_1</del>/R249s/1'>R249S</scene>, the core domain incorporating R249S and a second-site suppressor mutation H168R (referred to as the double mutant R249S/H168R) and its sequence-specific complex with DNA and of the triple mutant R249S/H168R/T123A. The structural studies were accompanied by transactivation and apoptosis experiments. The crystal structures show that the region at the vicinity of the mutation site in the R249S mutant displays a range of conformations [wild-type (wt) and several mutant-type conformations] due to the loss of stabilizing interactions mediated by R249 in the wt protein. As a consequence, the protein surface that is critical to the formation of functional p53-DNA complexes, through protein-protein and protein-DNA interactions, is largely distorted in the mutant conformations, thus explaining the protein's "loss of function" as a transcription factor. The structure of this region is restored in both R249S/H168R and R249S/H168R/T123A and is further stabilized in the complex of R249S/H168R with DNA. Our functional data show that the introduction of H168R as a second-site suppressor mutation partially restores the transactivation capacity of the protein and that this effect is further amplified by the addition of a third-site mutation T123A. These findings together with previously reported data on wt and mutant p53 provide a structural framework for understanding p53 dysfunction as a result of oncogenic mutations and its rescue by suppressor mutations and for a potential drug design aimed at restoring wt activity to aberrant p53 proteins.</div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>The tumor suppressor protein p53 is mutated in more than 50% of invasive cancers. About 30% of the mutations are found in six major "hot spot" codons located in its DNA binding core domain. To gain structural insight into the deleterious effects of such mutations and their rescue by suppressor mutations, we determined the crystal structures of the p53 core domain incorporating the hot spot mutation <scene name='<ins style="color: red; font-weight: bold; text-decoration: none;">Ann_Taylor/sandbox_1</ins>/R249s/1'>R249S</scene>, the core domain incorporating R249S and a second-site suppressor mutation H168R (referred to as the double mutant R249S/H168R) and its sequence-specific complex with DNA and of the triple mutant R249S/H168R/T123A. The structural studies were accompanied by transactivation and apoptosis experiments. The crystal structures show that the region at the vicinity of the mutation site in the R249S mutant displays a range of conformations [wild-type (wt) and several mutant-type conformations] due to the loss of stabilizing interactions mediated by R249 in the wt protein. As a consequence, the protein surface that is critical to the formation of functional p53-DNA complexes, through protein-protein and protein-DNA interactions, is largely distorted in the mutant conformations, thus explaining the protein's "loss of function" as a transcription factor. The structure of this region is restored in both R249S/H168R and R249S/H168R/T123A and is further stabilized in the complex of R249S/H168R with DNA. Our functional data show that the introduction of H168R as a second-site suppressor mutation partially restores the transactivation capacity of the protein and that this effect is further amplified by the addition of a third-site mutation T123A. These findings together with previously reported data on wt and mutant p53 provide a structural framework for understanding p53 dysfunction as a result of oncogenic mutations and its rescue by suppressor mutations and for a potential drug design aimed at restoring wt activity to aberrant p53 proteins.</div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Structural basis of restoring sequence-specific DNA binding and transactivation to mutant p53 by suppressor mutations., Suad O, Rozenberg H, Brosh R, Diskin-Posner Y, Kessler N, Shimon LJ, Frolow F, Liran A, Rotter V, Shakked Z, J Mol Biol. 2009 Jan 9;385(1):249-65. Epub 2008 Oct 30. PMID:18996393</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Structural basis of restoring sequence-specific DNA binding and transactivation to mutant p53 by suppressor mutations., Suad O, Rozenberg H, Brosh R, Diskin-Posner Y, Kessler N, Shimon LJ, Frolow F, Liran A, Rotter V, Shakked Z, J Mol Biol. 2009 Jan 9;385(1):249-65. Epub 2008 Oct 30. PMID:18996393</div></td></tr> </table> Mon, 31 Aug 2009 16:08:45 GMT Ann Taylor http://52.214.119.220/wiki/index.php/Talk:Jonathan_O%27Donnell_sandbox_1 Ann Taylor at 16:06, 31 August 2009 http://52.214.119.220/wiki/index.php?title=Jonathan_O%27Donnell_sandbox_1&diff=990533&oldid=prev <p></p> <table style="background-color: white; color:black;"> <col class='diff-marker' /> <col class='diff-content' /> <col class='diff-marker' /> <col class='diff-content' /> <tr> <td colspan='2' style="background-color: white; color:black;">←Older revision</td> <td colspan='2' style="background-color: white; color:black;">Revision as of 16:06, 31 August 2009</td> </tr> <tr><td colspan="2" class="diff-lineno">Line 12:</td> <td colspan="2" class="diff-lineno">Line 12:</td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>The tumor suppressor protein p53 is mutated in more than 50% of invasive cancers. About 30% of the mutations are found in six major "hot spot" codons located in its DNA binding core domain. To gain structural insight into the deleterious effects of such mutations and their rescue by suppressor mutations, we determined the crystal structures of the p53 core domain incorporating the hot spot mutation R249S, the core domain incorporating R249S and a second-site suppressor mutation H168R (referred to as the double mutant R249S/H168R) and its sequence-specific complex with DNA and of the triple mutant R249S/H168R/T123A. The structural studies were accompanied by transactivation and apoptosis experiments. The crystal structures show that the region at the vicinity of the mutation site in the R249S mutant displays a range of conformations [wild-type (wt) and several mutant-type conformations] due to the loss of stabilizing interactions mediated by R249 in the wt protein. As a consequence, the protein surface that is critical to the formation of functional p53-DNA complexes, through protein-protein and protein-DNA interactions, is largely distorted in the mutant conformations, thus explaining the protein's "loss of function" as a transcription factor. The structure of this region is restored in both R249S/H168R and R249S/H168R/T123A and is further stabilized in the complex of R249S/H168R with DNA. Our functional data show that the introduction of H168R as a second-site suppressor mutation partially restores the transactivation capacity of the protein and that this effect is further amplified by the addition of a third-site mutation T123A. These findings together with previously reported data on wt and mutant p53 provide a structural framework for understanding p53 dysfunction as a result of oncogenic mutations and its rescue by suppressor mutations and for a potential drug design aimed at restoring wt activity to aberrant p53 proteins.</div></td><td class='diff-marker'>+</td><td style="background: #cfc; color:black; font-size: smaller;"><div>The tumor suppressor protein p53 is mutated in more than 50% of invasive cancers. About 30% of the mutations are found in six major "hot spot" codons located in its DNA binding core domain. To gain structural insight into the deleterious effects of such mutations and their rescue by suppressor mutations, we determined the crystal structures of the p53 core domain incorporating the hot spot mutation <ins style="color: red; font-weight: bold; text-decoration: none;"><scene name='Jonathan_O'Donnell_sandbox_1/R249s/1'></ins>R249S<ins style="color: red; font-weight: bold; text-decoration: none;"></scene></ins>, the core domain incorporating R249S and a second-site suppressor mutation H168R (referred to as the double mutant R249S/H168R) and its sequence-specific complex with DNA and of the triple mutant R249S/H168R/T123A. The structural studies were accompanied by transactivation and apoptosis experiments. The crystal structures show that the region at the vicinity of the mutation site in the R249S mutant displays a range of conformations [wild-type (wt) and several mutant-type conformations] due to the loss of stabilizing interactions mediated by R249 in the wt protein. As a consequence, the protein surface that is critical to the formation of functional p53-DNA complexes, through protein-protein and protein-DNA interactions, is largely distorted in the mutant conformations, thus explaining the protein's "loss of function" as a transcription factor. The structure of this region is restored in both R249S/H168R and R249S/H168R/T123A and is further stabilized in the complex of R249S/H168R with DNA. Our functional data show that the introduction of H168R as a second-site suppressor mutation partially restores the transactivation capacity of the protein and that this effect is further amplified by the addition of a third-site mutation T123A. These findings together with previously reported data on wt and mutant p53 provide a structural framework for understanding p53 dysfunction as a result of oncogenic mutations and its rescue by suppressor mutations and for a potential drug design aimed at restoring wt activity to aberrant p53 proteins.</div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Structural basis of restoring sequence-specific DNA binding and transactivation to mutant p53 by suppressor mutations., Suad O, Rozenberg H, Brosh R, Diskin-Posner Y, Kessler N, Shimon LJ, Frolow F, Liran A, Rotter V, Shakked Z, J Mol Biol. 2009 Jan 9;385(1):249-65. Epub 2008 Oct 30. PMID:18996393</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>Structural basis of restoring sequence-specific DNA binding and transactivation to mutant p53 by suppressor mutations., Suad O, Rozenberg H, Brosh R, Diskin-Posner Y, Kessler N, Shimon LJ, Frolow F, Liran A, Rotter V, Shakked Z, J Mol Biol. 2009 Jan 9;385(1):249-65. Epub 2008 Oct 30. PMID:18996393</div></td></tr> </table> Mon, 31 Aug 2009 16:06:30 GMT Ann Taylor http://52.214.119.220/wiki/index.php/Talk:Jonathan_O%27Donnell_sandbox_1 Ann Taylor at 15:50, 31 August 2009 http://52.214.119.220/wiki/index.php?title=Jonathan_O%27Donnell_sandbox_1&diff=990530&oldid=prev <p></p> <table style="background-color: white; color:black;"> <col class='diff-marker' /> <col class='diff-content' /> <col class='diff-marker' /> <col class='diff-content' /> <tr> <td colspan='2' style="background-color: white; color:black;">←Older revision</td> <td colspan='2' style="background-color: white; color:black;">Revision as of 15:50, 31 August 2009</td> </tr> <tr><td colspan="2" class="diff-lineno">Line 1:</td> <td colspan="2" class="diff-lineno">Line 1:</td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div>{{Seed}}</div></td><td colspan="2"> </td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>[[Image:3d06.jpg|left|200px]]</div></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"><div>[[Image:3d06.jpg|left|200px]]</div></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td colspan="2" class="diff-lineno">Line 13:</td> <td colspan="2" class="diff-lineno">Line 12:</td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td><td class='diff-marker'> </td><td style="background: #eee; color:black; font-size: smaller;"></td></tr> <tr><td class='diff-marker'>-</td><td style="background: #ffa; color:black; font-size: smaller;"><div><del style="color: red; font-weight: bold; text-decoration: none;"><br /> {{STRUCTURE_3d06| PDB=3d06 | SCENE= }} <br /> <br /> ===Human p53 core domain with hot spot mutation R249S (I)===<br /> <br /> <br /> <br /> {{ABSTRACT_PUBMED_18996393}}<br /> <br /> ==Disease==<br /> Known disease associated with this structure: Adrenal cortical carcinoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Breast cancer OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Colorectal cancer OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Hepatocellular carcinoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Histiocytoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Li-Fraumeni syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Multiple malignancy syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Nasopharyngeal carcinoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Osteosarcoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Pancreatic cancer OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Thyroid carcinoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]]<br /> <br /> ==About this Structure==<br /> 3D06 is a 1 chain structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3D06 OCA]. <br /> <br /> ==Reference==<br /> <ref group="xtra">PMID:18996393</ref><references group="xtra"/><br /> [[Category: Homo sapiens]]<br /> [[Category: Frolow, F.]]<br /> [[Category: Rozenberg, H.]]<br /> [[Category: Shakked, Z.]]<br /> [[Category: Shimon, L J.W.]]<br /> [[Category: Suad, O.]]<br /> [[Category: Acetylation]]<br /> [[Category: Activator]]<br /> [[Category: Alternative splicing]]<br /> [[Category: Anti-oncogene]]<br /> [[Category: Apoptosis]]<br /> [[Category: Cell cycle]]<br /> [[Category: Covalent protein-rna linkage]]<br /> [[Category: Cytoplasm]]<br /> [[Category: Disease mutation]]<br /> [[Category: Dna-binding]]<br /> [[Category: Endoplasmic reticulum]]<br /> [[Category: Glycoprotein]]<br /> [[Category: Host-virus interaction]]<br /> [[Category: Li-fraumeni syndrome]]<br /> [[Category: Loop-sheet-helix motif]]<br /> [[Category: Metal-binding]]<br /> [[Category: Methylation]]<br /> [[Category: Mutant protein]]<br /> [[Category: Nucleus]]<br /> [[Category: P53]]<br /> [[Category: Phosphoprotein]]<br /> [[Category: Polymorphism]]<br /> [[Category: Transcription]]<br /> [[Category: Transcription regulation]]<br /> [[Category: Ubl conjugation]]<br /> [[Category: Zinc]]<br /> <br /> ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 21 10:44:12 2009''</div> Mon, 31 Aug 2009 15:47:10 GMT Ann Taylor http://52.214.119.220/wiki/index.php/Talk:Jonathan_O%27Donnell_sandbox_1