1gwr: Difference between revisions
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==Overview== | ==Overview== | ||
The activation function 2/ligand-dependent interaction between nuclear, receptors and their coregulators is mediated by a short consensus motif, the so-called nuclear receptor (NR) box. Nuclear receptors exhibit, distinct preferences for such motifs depending both on the bound ligand, and on the NR box sequence. To better understand the structural basis of, motif recognition, we characterized the interaction between estrogen, receptor alpha and the NR box regions of the p160 coactivator TIF2. We, have determined the crystal structures of complexes between the, ligand-binding domain of estrogen receptor alpha and 12-mer peptides from, the Box B2 and Box B3 regions of TIF2. Surprisingly, the Box B3 module, displays an unexpected binding mode that is distinct from the canonical, LXXLL interaction observed in other ligand-binding domain/NR box crystal, structures. The peptide is shifted along the coactivator binding site in, such a way that the interaction motif becomes LXXYL rather than the, classical LXXLL. However, analysis of the binding properties of wild type, NR box peptides, as well as mutant peptides designed to probe the Box B3, orientation, suggests that the Box B3 peptide primarily adopts the, "classical" LXXLL orientation in solution. These results highlight the, potential difficulties in interpretation of protein-protein interactions, based on co-crystal structures using short peptide motifs. | The activation function 2/ligand-dependent interaction between nuclear, receptors and their coregulators is mediated by a short consensus motif, the so-called nuclear receptor (NR) box. Nuclear receptors exhibit, distinct preferences for such motifs depending both on the bound ligand, and on the NR box sequence. To better understand the structural basis of, motif recognition, we characterized the interaction between estrogen, receptor alpha and the NR box regions of the p160 coactivator TIF2. We, have determined the crystal structures of complexes between the, ligand-binding domain of estrogen receptor alpha and 12-mer peptides from, the Box B2 and Box B3 regions of TIF2. Surprisingly, the Box B3 module, displays an unexpected binding mode that is distinct from the canonical, LXXLL interaction observed in other ligand-binding domain/NR box crystal, structures. The peptide is shifted along the coactivator binding site in, such a way that the interaction motif becomes LXXYL rather than the, classical LXXLL. However, analysis of the binding properties of wild type, NR box peptides, as well as mutant peptides designed to probe the Box B3, orientation, suggests that the Box B3 peptide primarily adopts the, "classical" LXXLL orientation in solution. These results highlight the, potential difficulties in interpretation of protein-protein interactions, based on co-crystal structures using short peptide motifs. | ||
==Disease== | |||
Known diseases associated with this structure: Atherosclerosis, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=133430 133430]], Breast cancer OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=133430 133430]], Estrogen resistance OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=133430 133430]], HDL response to hormone replacement, augmented OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=133430 133430]], Migraine, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=133430 133430]], Myocardial infarction, susceptibility to OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=133430 133430]] | |||
==About this Structure== | ==About this Structure== | ||
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[[Category: zinc finger]] | [[Category: zinc finger]] | ||
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 17:09:48 2007'' | ||
Revision as of 18:03, 12 November 2007
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HUMAN OESTROGEN RECEPTOR ALPHA LIGAND-BINDING DOMAIN IN COMPLEX WITH 17BETA-OESTRADIOL AND TIF2 NRBOX3 PEPTIDE
OverviewOverview
The activation function 2/ligand-dependent interaction between nuclear, receptors and their coregulators is mediated by a short consensus motif, the so-called nuclear receptor (NR) box. Nuclear receptors exhibit, distinct preferences for such motifs depending both on the bound ligand, and on the NR box sequence. To better understand the structural basis of, motif recognition, we characterized the interaction between estrogen, receptor alpha and the NR box regions of the p160 coactivator TIF2. We, have determined the crystal structures of complexes between the, ligand-binding domain of estrogen receptor alpha and 12-mer peptides from, the Box B2 and Box B3 regions of TIF2. Surprisingly, the Box B3 module, displays an unexpected binding mode that is distinct from the canonical, LXXLL interaction observed in other ligand-binding domain/NR box crystal, structures. The peptide is shifted along the coactivator binding site in, such a way that the interaction motif becomes LXXYL rather than the, classical LXXLL. However, analysis of the binding properties of wild type, NR box peptides, as well as mutant peptides designed to probe the Box B3, orientation, suggests that the Box B3 peptide primarily adopts the, "classical" LXXLL orientation in solution. These results highlight the, potential difficulties in interpretation of protein-protein interactions, based on co-crystal structures using short peptide motifs.
DiseaseDisease
Known diseases associated with this structure: Atherosclerosis, susceptibility to OMIM:[133430], Breast cancer OMIM:[133430], Estrogen resistance OMIM:[133430], HDL response to hormone replacement, augmented OMIM:[133430], Migraine, susceptibility to OMIM:[133430], Myocardial infarction, susceptibility to OMIM:[133430]
About this StructureAbout this Structure
1GWR is a Protein complex structure of sequences from Homo sapiens with EST as ligand. Structure known Active Site: ESA. Full crystallographic information is available from OCA.
ReferenceReference
Interaction of transcriptional intermediary factor 2 nuclear receptor box peptides with the coactivator binding site of estrogen receptor alpha., Warnmark A, Treuter E, Gustafsson JA, Hubbard RE, Brzozowski AM, Pike AC, J Biol Chem. 2002 Jun 14;277(24):21862-8. Epub 2002 Apr 5. PMID:11937504
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