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<StructureSection load='1tup' size='350' side='right' scene='26/26327/Initl/2' caption='Human p53 DNA-binding domain complex with DNA and Zn+2 ions (grey) (PDB Code [[1tup]])'>
<StructureSection load='' size='350' side='right' scene='26/26327/P53-dna/2' caption='Human p53 DNA-binding domain complex with DNA and Zn+2 ion (magenta) (PDB Code [[1tup]])'>
[[Image:P53_DNA.png|left|200px]]
 
__TOC__
__TOC__
==p53 Tumor Suppressor Protein (PDB ID [[1tup]])==
==p53 Tumor Suppressor Protein (PDB ID [[1tup]])==
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In a normal cell, p53 is inactivated by its negative regulatory mdm2 (hdm2 in humans) and it is found at low levels. When DNA damage is sensed, p53's level rises. p53 binds to many regulatory sites in the genome and begins production of proteins that stop cell division until the damage is repaired. If the damage is irreparable, p53 initiates the process called programmed cell death, apoptosis, permanently removing the damage.  
In a normal cell, p53 is inactivated by its negative regulatory mdm2 (hdm2 in humans) and it is found at low levels. When DNA damage is sensed, p53's level rises. p53 binds to many regulatory sites in the genome and begins production of proteins that stop cell division until the damage is repaired. If the damage is irreparable, p53 initiates the process called programmed cell death, apoptosis, permanently removing the damage.  


In most cases of human cancer, p53 mutations have been observed. Most of the p53 mutations that may result in cancer are found in and around the DNA-binding surface of the protein. The most common mutation changes can be seen in a close up view of the <scene name='26/26327/B_chain_and_dna/5'>DNA binding domain with DNA </scene> color coded N to C (in rainbow colors), with the amino <scene name='26/26327/B_chain_and_dna/4'>R248</scene> (as space filling spheres) interacting with DNA. When mutated to another amino acid, this interaction is lost. Other residues associated with cancer-causing mutations are arginine <scene name='26/26327/B_chain_and_dna/6'>175, 249, 273, 282 and glycine 245</scene>. The figure at the top shows interaction of the DNA-binding domain with DNA. Key residues associated with mutations are represented by magenta spheres.
In most cases of human cancer, p53 mutations have been observed. Most of the p53 mutations that may result in cancer are found in and around the DNA-binding surface of the protein. The most common mutation changes can be seen in a close up view of the <scene name='26/26327/B_chain_and_dna/5'>DNA binding domain with DNA </scene> color coded N to C (in rainbow colors), with the amino <scene name='26/26327/B_chain_and_dna/4'>R248</scene> (as space filling spheres) interacting with DNA. When mutated to another amino acid, this interaction is lost. Other key residues associated with cancer-causing mutations are <scene name='26/26327/B_chain_and_dna/8'>175, 249, 273, 282 and glycine 245</scene> represented by magenta spheres.


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[[Image:P53_surface_charge.png | left | 400 px | thumb]]
{{Clear}}


=='''Surface charge of the DNA binding domain'''==
=='''Surface charge of the DNA binding domain'''==


The figure at the left shows the surface charge of the p53 DNA-binding domain. It is rich in arginine amino acids that interact with DNA, and this causes its surface to be positively charged. This domain recognizes specific regulatory sites on the DNA. The flexible structure of p53 allows it to bind to many different variants of binding sites, allowing it to regulate transcription at many places in the genome.
[[Image:P53_surface_charge.png | left | 250 px | thumb]]The figure at the left shows the surface charge of the p53 DNA-binding domain )Charged: red - negative; blue - positive). It is rich in arginine amino acids that interact with DNA, and this causes its surface to be positively charged. This domain recognizes specific regulatory sites on the DNA. The flexible structure of p53 allows it to bind to many different variants of binding sites, allowing it to regulate transcription at many places in the genome.




<scene name='Sandbox/P53_dna_binding_domain/1'>Click Here to view a Three-dimensional Representation of the DNA-binding Domain Bound to DNA</scene>
There is a Zn-binding motif on p53. The p53 Zn atom is coordinated by residues <scene name='26/26327/B_chain_and_dna/12'>C176, H179, C238, and C242</scene> that are located on two loops, respectively. It is conceivable that the zinc plays a role in stabilizing the two loops through
coordination. The Zn has been represented as a magenta sphere, and R248 in space filling, in the scene at the right.
 
==3D structures of p53==
[[P53 3D structures]]


There is a Zn-binding motif on p53. The p53 Zn atom is coordinated by residues
C176, H179, C238, and C242 that are located on two loops, respectively. It is conceivable that the
zinc plays a role in stabilizing the two loops through
coordination. The Zn has been represented as a red sphere in the figure at the right.
</StructureSection>
</StructureSection>
==3D structures of p53 (Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}) ==
{{#tree:id=OrganizedByTopic|openlevels=0|
*p53 DNA-binding domain
** [[2xwr]], [[2ocj]], [[2ybg]] – h-p53 DBD – human<BR />
** [[2fej]] - h-p53 DBD - NMR<BR />
** [[2wgx]], [[3d05]], [[3d06]], [[3d07]], [[3d08]], [[3d09]], [[2pcx]], [[2j1w]], [[2j1x]], [[2j1y]], [[2j1z]], [[2j20]], [[2j21]], [[2bim]], [[2bin]], [[2bio]], [[2bip]], [[2biq]], [[1uol]], [[4kvp]], [[4lo9]], [[4loe]], [[4lof]], [[4ibq]], [[4ibs]], [[4ibt]], [[4iby]], [[4ibz]], [[4ijt]], [[4mzi]] - h-p53 DBD (mutant) <BR />
** [[1hs5]] - h-p53 residues 324-357 - NMR<BR />
** [[3q01]] - h-p53 DBD + TD<br />
** [[2ioi]], [[2ioo]], [[1hu8]] – m-p53 DBD – mouse<BR />
** [[1t4w]] – p53-like DBD – ''Caenoharbditis elegans''
* p53 DNA-binding domain complex with DNA
** [[3igk]], [[3igl]], [[3kz8]], [[3kmd]], [[2ac0]], [[2ady]], [[2ahi]], [[2ata]], [[1tsr]], [[1tup]], [[4hje]] – h-p53 DBD + DNA<BR />
** [[3d0a]], [[3ts8]], [[4ibu]], [[4ibv]], [[4ibw]] - h-p53 DBD (mutant) + DNA<BR />
** [[3q05]], [[3q06]] - h-p53 DBD + TD + DNA<br />
** [[3exj]], [[3exl]], [[2p52]], [[2geq]] – m-p53 DBD + DNA
* p53 DNA-binding domain complex with small molecule
** [[2x0u]], [[2x0v]], [[2x0w]], [[4agl]], [[4agm]], [[4agn]], [[4ago]], [[4agp]], [[4agq]] – h-p53 DBD (mutant) + benzene derivative<BR />
** [[3zme]] - h-p53 DBD (mutant) + pyrazol derivative<br />
** [[2vuk]] - h-p53 DBD + drug<BR />
** [[2iom]] - m-p53 DBD + propanol
* p53 DNA-binding domain complex with protein<br />
** [[2k8f]] – h-p53 residues 1-39 + histone acetyltransferase (mutant) – NMR<BR />
** [[2h1l]] - h-p53 DBD + large T antigen<BR />
** [[1ycs]] - h-p53 DBD + 53BP2<BR />
** [[1gzh]], [[1kzy]] - h-p53 DBD + tumor suppressor p53-binding protein<br />
* p53 transactivation domain
** [[2z5s]], [[2z5t]] - h-p53 TAD + MDM4 protein<br />
** [[1ycq]], [[1ycr]] - h-p53 TAD + MDM2 protein<br />
** [[2l14]] – h-p53 TAD + CREB-binding protein<br />
** [[2gs0]] – h-p53 TAD + RNA polymerase II transcription factor
* p53 tetramerization domain
** [[2j0z]], [[3sak]], [[1sae]], [[1saf]], [[1sak]], [[1sal]], [[1olh]], [[1pes]], [[1pet]], [[1olg]] – h-p53 TD – NMR<BR />
** [[1c26]], [[1aie]] - h-p53 TD<BR />
** [[2j10]], [[2j11]], [[1a1u]] - h-p53 TD (mutant) – NMR<BR />
* p53 tetramerization+DBD domains
** [[4mzr]] – h-p53 + DNA<br />
}}


==Additional Resources==
==Additional Resources==

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Eran Hodis, Mary Ball, David Canner, Joel L. Sussman, Michal Harel, Alexander Berchansky
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