2d82
From Proteopedia
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'''Target Structure-Based Discovery of Small Molecules that Block Human p53 and CREB Binding Protein (CBP) Association'''<br /> | '''Target Structure-Based Discovery of Small Molecules that Block Human p53 and CREB Binding Protein (CBP) Association'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Lysine acetylation of human tumor suppressor p53 in response to cellular | + | Lysine acetylation of human tumor suppressor p53 in response to cellular stress signals is required for its function as a transcription factor that regulates cell cycle arrest, senescence, or apoptosis. Here, we report small molecules that block lysine 382-acetylated p53 association with the bromodomain of the coactivator CBP, an interaction essential for p53-induced transcription of the cell cycle inhibitor p21 in response to DNA damage. These chemicals were discovered in target structure-guided nuclear magnetic resonance spectroscopy screening of a focused chemical library constructed based on the structural knowledge of CBP bromodomain/p53-AcK382 binding. Structural characterization shows that these chemicals inhibit CBP/p53 association by binding to the acetyl-lysine binding site of the bromodomain. Cell-based functional assays demonstrate that the lead chemicals can modulate p53 stability and function in response to DNA damage. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2D82 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with TTR as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Histone_acetyltransferase Histone acetyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.48 2.3.1.48] Full crystallographic information is available from [http:// | + | 2D82 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=TTR:'>TTR</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Histone_acetyltransferase Histone acetyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.1.48 2.3.1.48] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2D82 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Liu, W | + | [[Category: Liu, W J.]] |
| - | [[Category: Manfredi, J | + | [[Category: Manfredi, J J.]] |
[[Category: Mujtaba, S.]] | [[Category: Mujtaba, S.]] | ||
[[Category: Resnick-Silverman, L.]] | [[Category: Resnick-Silverman, L.]] | ||
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[[Category: Yan, S.]] | [[Category: Yan, S.]] | ||
[[Category: Zeng, L.]] | [[Category: Zeng, L.]] | ||
| - | [[Category: Zhou, M | + | [[Category: Zhou, M M.]] |
[[Category: TTR]] | [[Category: TTR]] | ||
[[Category: 3]] | [[Category: 3]] | ||
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[[Category: p53]] | [[Category: p53]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:56:04 2008'' |
Revision as of 14:56, 21 February 2008
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Target Structure-Based Discovery of Small Molecules that Block Human p53 and CREB Binding Protein (CBP) Association
Contents |
Overview
Lysine acetylation of human tumor suppressor p53 in response to cellular stress signals is required for its function as a transcription factor that regulates cell cycle arrest, senescence, or apoptosis. Here, we report small molecules that block lysine 382-acetylated p53 association with the bromodomain of the coactivator CBP, an interaction essential for p53-induced transcription of the cell cycle inhibitor p21 in response to DNA damage. These chemicals were discovered in target structure-guided nuclear magnetic resonance spectroscopy screening of a focused chemical library constructed based on the structural knowledge of CBP bromodomain/p53-AcK382 binding. Structural characterization shows that these chemicals inhibit CBP/p53 association by binding to the acetyl-lysine binding site of the bromodomain. Cell-based functional assays demonstrate that the lead chemicals can modulate p53 stability and function in response to DNA damage.
Disease
Known diseases associated with this structure: Blue-cone monochromacy OMIM:[303900], Colorblindness, protan OMIM:[303900], Rubenstein-Taybi syndrome OMIM:[600140]
About this Structure
2D82 is a Single protein structure of sequence from Homo sapiens with as ligand. Active as Histone acetyltransferase, with EC number 2.3.1.48 Full crystallographic information is available from OCA.
Reference
Target structure-based discovery of small molecules that block human p53 and CREB binding protein association., Sachchidanand, Resnick-Silverman L, Yan S, Mutjaba S, Liu WJ, Zeng L, Manfredi JJ, Zhou MM, Chem Biol. 2006 Jan;13(1):81-90. PMID:16426974
Page seeded by OCA on Thu Feb 21 16:56:04 2008
Categories: Histone acetyltransferase | Homo sapiens | Single protein | Liu, W J. | Manfredi, J J. | Mujtaba, S. | Resnick-Silverman, L. | Sachchidanand | Yan, S. | Zeng, L. | Zhou, M M. | TTR | 3 | 4 | 9-acetyl-2 | 9-tetrahydro-carbazol-1-one | Bromodomain | Cbp | Chemical ligand | Creb | Nmr structure | P53
