1x2r
From Proteopedia
(New page: 200px<br /><applet load="1x2r" size="450" color="white" frame="true" align="right" spinBox="true" caption="1x2r, resolution 1.7Å" /> '''Structural basis for ...) |
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| - | [[Image:1x2r.gif|left|200px]]<br /><applet load="1x2r" size=" | + | [[Image:1x2r.gif|left|200px]]<br /><applet load="1x2r" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1x2r, resolution 1.7Å" /> | caption="1x2r, resolution 1.7Å" /> | ||
'''Structural basis for the defects of human lung cancer somatic mutations in the repression activity of Keap1 on Nrf2'''<br /> | '''Structural basis for the defects of human lung cancer somatic mutations in the repression activity of Keap1 on Nrf2'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Nrf2 regulates the cellular oxidative stress response, whereas Keap1 | + | Nrf2 regulates the cellular oxidative stress response, whereas Keap1 represses Nrf2 through its molecular interaction. To elucidate the molecular mechanism of the Keap1 and Nrf2 interaction, we resolved the six-bladed beta propeller crystal structure of the Kelch/DGR and CTR domains of mouse Keap1 and revealed that extensive inter- and intrablade hydrogen bonds maintain the structural integrity and proper association of Keap1 with Nrf2. A peptide containing the ETGE motif of Nrf2 binds the beta propeller of Keap1 at the entrance of the central cavity on the bottom side via electrostatic interactions with conserved arginine residues. We found a somatic mutation and a gene variation in human lung cancer cells that change glycine to cysteine in the DGR domain, introducing local conformational changes that reduce Keap1's affinity for Nrf2. These results provide a structural basis for the loss of Keap1 function and gain of Nrf2 function. |
==About this Structure== | ==About this Structure== | ||
| - | 1X2R is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with SO4 as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http:// | + | 1X2R is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus] with <scene name='pdbligand=SO4:'>SO4</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1X2R OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Mus musculus]] | [[Category: Mus musculus]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
| - | [[Category: Kang, M | + | [[Category: Kang, M I.]] |
[[Category: Kobayashi, A.]] | [[Category: Kobayashi, A.]] | ||
[[Category: Nakamura, Y.]] | [[Category: Nakamura, Y.]] | ||
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[[Category: Ohtsuji, M.]] | [[Category: Ohtsuji, M.]] | ||
[[Category: Padmanabhan, B.]] | [[Category: Padmanabhan, B.]] | ||
| - | [[Category: RSGI, RIKEN | + | [[Category: RSGI, RIKEN Structural Genomics/Proteomics Initiative.]] |
[[Category: Scharlock, M.]] | [[Category: Scharlock, M.]] | ||
| - | [[Category: Tong, K | + | [[Category: Tong, K I.]] |
[[Category: Yamamoto, M.]] | [[Category: Yamamoto, M.]] | ||
[[Category: Yokoyama, S.]] | [[Category: Yokoyama, S.]] | ||
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[[Category: structural genomics]] | [[Category: structural genomics]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:50:33 2008'' |
Revision as of 13:50, 21 February 2008
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Structural basis for the defects of human lung cancer somatic mutations in the repression activity of Keap1 on Nrf2
Overview
Nrf2 regulates the cellular oxidative stress response, whereas Keap1 represses Nrf2 through its molecular interaction. To elucidate the molecular mechanism of the Keap1 and Nrf2 interaction, we resolved the six-bladed beta propeller crystal structure of the Kelch/DGR and CTR domains of mouse Keap1 and revealed that extensive inter- and intrablade hydrogen bonds maintain the structural integrity and proper association of Keap1 with Nrf2. A peptide containing the ETGE motif of Nrf2 binds the beta propeller of Keap1 at the entrance of the central cavity on the bottom side via electrostatic interactions with conserved arginine residues. We found a somatic mutation and a gene variation in human lung cancer cells that change glycine to cysteine in the DGR domain, introducing local conformational changes that reduce Keap1's affinity for Nrf2. These results provide a structural basis for the loss of Keap1 function and gain of Nrf2 function.
About this Structure
1X2R is a Protein complex structure of sequences from Mus musculus with as ligand. Full crystallographic information is available from OCA.
Reference
Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer., Padmanabhan B, Tong KI, Ohta T, Nakamura Y, Scharlock M, Ohtsuji M, Kang MI, Kobayashi A, Yokoyama S, Yamamoto M, Mol Cell. 2006 Mar 3;21(5):689-700. PMID:16507366
Page seeded by OCA on Thu Feb 21 15:50:33 2008
Categories: Mus musculus | Protein complex | Kang, M I. | Kobayashi, A. | Nakamura, Y. | Ohta, T. | Ohtsuji, M. | Padmanabhan, B. | RSGI, RIKEN Structural Genomics/Proteomics Initiative. | Scharlock, M. | Tong, K I. | Yamamoto, M. | Yokoyama, S. | SO4 | Beta propeller | National project on protein structural and functional analyses | Nppsfa | Riken structural genomics/proteomics initiative | Rsgi | Structural genomics
