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1X2J

Structural basis for the defects of human lung cancer somatic mutations in the repression activity of Keap1 on Nrf2

Summary for 1X2J
Entry DOI10.2210/pdb1x2j/pdb
Related1X2R
DescriptorKelch-like ECH-associated protein 1, SULFATE ION (3 entities in total)
Functional Keywordsbeta propeller, structural genomics, nppsfa, national project on protein structural and functional analyses, riken structural genomics/proteomics initiative, rsgi, transcription
Biological sourceMus musculus (house mouse)
Cellular locationCytoplasm: Q9Z2X8
Total number of polymer chains1
Total formula weight35480.41
Authors
Primary citationPadmanabhan, B.,Tong, K.I.,Ohta, T.,Nakamura, Y.,Scharlock, M.,Ohtsuji, M.,Kang, M.-I.,Kobayashi, A.,Yokoyama, S.,Yamamoto, M.
Structural basis for defects of keap1 activity provoked by its point mutations in lung cancer
Mol.Cell, 21:689-700, 2006
Cited by
PubMed Abstract: 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.
PubMed: 16507366
DOI: 10.1016/j.molcel.2006.01.013
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.6 Å)
Structure validation

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