User:Ann Taylor/Sandbox 1: Difference between revisions

Line 1:

~~[[Image:3d06.jpg|left|200px]]~~

~~<!--~~

~~The line below this paragraph, containing "STRUCTURE_3d06", creates the "Structure Box" on the page.~~

~~You may change the PDB parameter (which sets the PDB file loaded into the applet)~~

~~or the SCENE parameter (which sets the initial scene displayed when the page is loaded),~~

~~or leave the SCENE parameter empty for the default display.~~

-->

===~~Human p53 core domain with hot spot mutation R249S (I)~~===

===Evaluating scenes representing the same structure===

This sandbox compiles several student-generated scenes that illustrate properties of the Gal4 repressor.

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='User:Ann_Taylor/Sandbox_1/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.

==Dimer==

~~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~~

The protein binds as a <scene name='92/925538/Dimer/2'>dimer</scene> to a symmetrical 17-base-pair sequence.

~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.~~

~~==Disease==~~

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]]

==~~About this Structure~~==

==Domains==

~~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]~~.

There is a compact <scene name='92/925538/Metal_binding_domain/5'>metal binding domain</scene> (residues 8-40), an <scene name='92/925538/Extended_linker/4'>extended linker</scene> (41-49), and an <scene name='92/925538/Alpha-helical_dimerization/2'>alpha-helical dimerization element</scene> (50-64).

==~~Reference~~==

<~~ref group~~=~~"xtra">PMID:18996393<~~/~~ref~~><~~references group="xtra"~~/>

~~[[Category: Homo sapiens]]~~

~~[[Category: Frolow, F~~.]]

==Metal binding==

~~[[Category: Rozenberg, H.]]~~

A small, Zn(2+)-containing domain recognizes a conserved CCG triplet at each end of the site through direct contacts with the major groove. The metal binding domain contains <scene name='92/925538/Cysteine_metal_binding/3'>cysteine residues</scene> that coordinate to the metal as shown as cadmium.

~~[[Category: Shakked, Z.]]~~

~~[[Category: Shimon, L J.W.]]~~

~~[[Category: Suad, O.]]~~

~~[[Category: Acetylation]]~~

==DNA/protein interaction==

~~[[Category: Activator]]~~

<scene name='92/925538/Dna_protein_interaction/3'>The DNA-Protein Interaction</scene> with all of the base pairs within 5 angstroms of the protein highlighted illustrates that the protein interacts with both strands of the UAS.

~~[[Category: Alternative splicing]]~~

~~[[Category: Anti-oncogene]]~~

~~[[Category: Apoptosis]]~~

~~[[Category: Cell cycle]]~~

~~[[Category: Covalent~~ protein~~-rna linkage]]~~

~~[[Category: Cytoplasm]]~~

~~[[Category: Disease mutation]]~~

~~[[Category: Dna-binding]]~~

~~[[Category: Endoplasmic reticulum]]~~

~~[[Category: Glycoprotein]]~~

~~[[Category: Host-virus~~ interaction]]

~~[[Category: Li~~-~~fraumeni syndrome]]~~

~~[[Category: Loop-sheet-helix motif]]~~

~~[[Category: Metal-binding]]~~

~~[[Category: Methylation]]~~

~~[[Category: Mutant~~ protein]]

~~[[Category: Nucleus]]~~

~~[[Category: P53]]~~

~~[[Category: Phosphoprotein]]~~

~~[[Category: Polymorphism]]~~

~~[[Category: Transcription]]~~

~~[[Category: Transcription regulation]]~~

~~[[Category: Ubl conjugation]]~~

~~[[Category: Zinc]]~~

@@ Line 1: / Line 1: @@
-[[Image:3d06.jpg|left|200px]]
-<!--
-The line below this paragraph, containing "STRUCTURE_3d06", creates the "Structure Box" on the page.
-You may change the PDB parameter (which sets the PDB file loaded into the applet)
-or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-or leave the SCENE parameter empty for the default display.
 -->
-{{STRUCTURE_3d06|  PDB=3d06  |  SCENE=  }}
+{{STRUCTURE_1d66|  PDB=1d66  |  SCENE=  }}
-===Human p53 core domain with hot spot mutation R249S (I)===
+===Evaluating scenes representing the same structure===
+This sandbox compiles several student-generated scenes that illustrate properties of the Gal4 repressor.
-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='User:Ann_Taylor/Sandbox_1/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.
+==Dimer==
-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
+The protein binds as a <scene name='92/925538/Dimer/2'>dimer</scene> to a symmetrical 17-base-pair sequence.
-From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
-==Disease==
-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]]
-==About this Structure==
+==Domains==
-D06 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].
+There is a compact <scene name='92/925538/Metal_binding_domain/5'>metal binding domain</scene> (residues 8-40), an <scene name='92/925538/Extended_linker/4'>extended linker</scene> (41-49), and an <scene name='92/925538/Alpha-helical_dimerization/2'>alpha-helical dimerization element</scene> (50-64).
-==Reference==
-<ref group="xtra">PMID:18996393</ref><references group="xtra"/>
-[[Category: Homo sapiens]]
-[[Category: Frolow, F.]]
+==Metal binding==
-[[Category: Rozenberg, H.]]
+A small, Zn(2+)-containing domain recognizes a conserved CCG triplet at each end of the site through direct contacts with the major groove. The metal binding domain contains <scene name='92/925538/Cysteine_metal_binding/3'>cysteine residues</scene> that coordinate to the metal as shown as cadmium.
-[[Category: Shakked, Z.]]
-[[Category: Shimon, L J.W.]]
-[[Category: Suad, O.]]
-[[Category: Acetylation]]
+==DNA/protein interaction==
-[[Category: Activator]]
+ <scene name='92/925538/Dna_protein_interaction/3'>The DNA-Protein Interaction</scene> with all of the base pairs within 5 angstroms of the protein highlighted illustrates that the protein interacts with both strands of the UAS.
-[[Category: Alternative splicing]]
-[[Category: Anti-oncogene]]
-[[Category: Apoptosis]]
-[[Category: Cell cycle]]
-[[Category: Covalent protein-rna linkage]]
-[[Category: Cytoplasm]]
-[[Category: Disease mutation]]
-[[Category: Dna-binding]]
-[[Category: Endoplasmic reticulum]]
-[[Category: Glycoprotein]]
-[[Category: Host-virus interaction]]
-[[Category: Li-fraumeni syndrome]]
-[[Category: Loop-sheet-helix motif]]
-[[Category: Metal-binding]]
-[[Category: Methylation]]
-[[Category: Mutant protein]]
-[[Category: Nucleus]]
-[[Category: P53]]
-[[Category: Phosphoprotein]]
-[[Category: Polymorphism]]
-[[Category: Transcription]]
-[[Category: Transcription regulation]]
-[[Category: Ubl conjugation]]
-[[Category: Zinc]]