P53-DNA Recognition: Difference between revisions
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===Major Groove Base Readout=== | ===Major Groove Base Readout=== | ||
[[Image:p53-motif.jpg|thumb|right|300px|Figure | [[Image:p53-motif.jpg|thumb|right|300px|Figure 5: p53 binding site motif with G/C base pairs most conserved. PLoS has provided permission for usage of this figure<ref>Horvath MM, Wang X, Resnick MA, Bell DA. Divergent evolution of human p53 binding sites: cell cycle versus apoptosis. PLoS Genet. 2007 Jul;3(7):e127. [http://www.ncbi.nlm.nih.gov/pubmed/17677004 PMID:17677004].</ref>.]] | ||
Protein side chains and base pairs form direct contacts in the major groove. Among which, the <scene name='Sandbox_Reserved_170/Arg280_contact/5'>contact between Arg280 and the guanine of the core element</scene> contributes most to binding specificity. This highly specific readout is due to the <scene name='Sandbox_Reserved_170/Arg280_contact/4'>bidentate hydrogen bond formed between Arg280 and guanine</scene>. As a result of this '''base readout''' the G/C base pairs in the CWWG core elements are the most conserved positions in p53 response elements ('''Figure | Protein side chains and base pairs form direct contacts in the major groove. Among which, the <scene name='Sandbox_Reserved_170/Arg280_contact/5'>contact between Arg280 and the guanine of the core element</scene> contributes most to binding specificity. This highly specific readout is due to the <scene name='Sandbox_Reserved_170/Arg280_contact/4'>bidentate hydrogen bond formed between Arg280 and guanine</scene>. As a result of this '''base readout''' the G/C base pairs in the CWWG core elements are the most conserved positions in p53 response elements ('''Figure 5'''). | ||
Another important contact is formed with the <scene name='Sandbox_Reserved_170/Lys_120/3'>Lys120 residue from the L1 loop of the protein</scene>. Lys120 is very important biologically because acetylation of this residue is known to trigger the apoptotic response of p53. | Another important contact is formed with the <scene name='Sandbox_Reserved_170/Lys_120/3'>Lys120 residue from the L1 loop of the protein</scene>. Lys120 is very important biologically because acetylation of this residue is known to trigger the apoptotic response of p53. | ||
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Another arginine residue, <scene name='Sandbox_Reserved_170/Arg273/2'>Arg273, contacts the phosphodiester backbone</scene> forming a salt bridge, and seems to be important for human p53-DNA binding. Moreover, Arg273 is the second most common missense mutation in human cancer ('''Figure 3'''). | Another arginine residue, <scene name='Sandbox_Reserved_170/Arg273/2'>Arg273, contacts the phosphodiester backbone</scene> forming a salt bridge, and seems to be important for human p53-DNA binding. Moreover, Arg273 is the second most common missense mutation in human cancer ('''Figure 3'''). | ||
[[Image:Kitayner-etal-Figure7.jpg|thumb|right|400px|Figure | [[Image:Kitayner-etal-Figure7.jpg|thumb|right|400px|Figure 6: DNA shape readout of narrow minor groove regions with enhanced electrostatic potential by Arg248. Nature Publishing Group has provided permission for usage of this figure<ref name='kitayner'/>.]] | ||
===Minor Groove Shape Readout=== | ===Minor Groove Shape Readout=== | ||
Most commonly, however, the residue Arg248 is found mutated in human tumors. <scene name='Sandbox_Reserved_170/Arg248/2'>Arg248 contacts the minor groove</scene> although it does not usually form hydrogen bonds with the bases. Arg248 was shown to recognize regions of narrow minor groove associated with enhanced negative electrostatic potential ('''Figure | Most commonly, however, the residue Arg248 is found mutated in human tumors. <scene name='Sandbox_Reserved_170/Arg248/2'>Arg248 contacts the minor groove</scene> although it does not usually form hydrogen bonds with the bases. Arg248 was shown to recognize regions of narrow minor groove associated with enhanced negative electrostatic potential ('''Figure 6''')<ref name='kitayner'/>. This observation provides a novel molecular explanation of the importance of Arg248 for p53-DNA binding and its role in cancer. The described mechanism known as '''shape readout''' was found to be broadly employed by arginine residues<ref name="nature">Rohs R, West SM, Sosinsky A, Liu P, Mann RS, Honig B. The role of DNA shape in protein-DNA recognition. Nature. 2009;461(7268):1248-53. [http://www.ncbi.nlm.nih.gov/pubmed/19865164 PMID:19865164].</ref>. | ||
==Hoogsteen vs. Watson-Crick Base Pair in p53 Binding Sites== | ==Hoogsteen vs. Watson-Crick Base Pair in p53 Binding Sites== | ||
