1jb6
From Proteopedia
(New page: 200px<br /><applet load="1jb6" size="450" color="white" frame="true" align="right" spinBox="true" caption="1jb6, resolution 1.70Å" /> '''Crystal Structure of...) |
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| - | [[Image:1jb6.jpg|left|200px]]<br /><applet load="1jb6" size=" | + | [[Image:1jb6.jpg|left|200px]]<br /><applet load="1jb6" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="1jb6, resolution 1.70Å" /> | caption="1jb6, resolution 1.70Å" /> | ||
'''Crystal Structure of Dimerization Domain (1-33) of HNF-1alpha'''<br /> | '''Crystal Structure of Dimerization Domain (1-33) of HNF-1alpha'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Maturity-onset diabetes mellitus of the young (MODY) is a human genetic | + | Maturity-onset diabetes mellitus of the young (MODY) is a human genetic syndrome most commonly due to mutations in hepatocyte nuclear factor-1alpha (HNF-1alpha). Here, we describe the crystal structure of the HNF-1alpha dimerization domain at 1.7 A resolution and assess its structural plasticity. The crystal's low solvent content (23%, v/v) leads to tight packing of peptides in the lattice. Two independent dimers, similar in structure, are formed in the unit cell by a 2-fold crystallographic symmetry axis. The dimers define a novel intertwined four-helix bundle (4HB). Each protomer contains two alpha-helices separated by a sharp non-canonical turn. Dimer-related alpha-helices form anti-parallel coiled-coils, including an N-terminal "mini-zipper" complementary in structure, symmetry and surface characteristics to transcriptional coactivator dimerization cofactor of HNF-1 (DCoH). A confluence of ten leucine side-chains (five per protomer) forms a hydrophobic core. Isotope-assisted NMR studies demonstrate that a similar intertwined dimer exists in solution. Comparison of structures obtained in multiple independent crystal forms indicates that the mini-zipper is a stable structural element, whereas the C-terminal alpha-helix can adopt a broad range of orientations. Segmental alignment of the mini-zipper (mean pairwise root-mean-square difference (rmsd) in C(alpha) coordinates of 0.29 A) is associated with a 2.1 A mean C(alpha) rmsd displacement of the C-terminal coiled-coil. The greatest C-terminal structural variation (4.1 A C(alpha) rmsd displacement) is observed in the DCoH-bound peptide. Diabetes-associated mutations perturb distinct structural features of the HNF-1alpha domain. One mutation (L12H) destabilizes the domain but preserves structural specificity. Adjoining H12 side-chains in a native-like dimer are predicted to alter the functional surface of the mini-zipper involved in DCoH recognition. The other mutation (G20R), by contrast, leads to a dimeric molten globule, as indicated by its 1H-NMR features and fluorescent binding of 1-anilino-8-naphthalene sulfonate. We propose that a glycine-specific turn configuration enables specific interactions between the mini-zipper and the C-terminal coiled-coil. |
==About this Structure== | ==About this Structure== | ||
| - | 1JB6 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ]. Full crystallographic information is available from [http:// | + | 1JB6 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/ ]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1JB6 OCA]. |
==Reference== | ==Reference== | ||
The dimerization domain of HNF-1alpha: structure and plasticity of an intertwined four-helix bundle with application to diabetes mellitus., Narayana N, Hua Q, Weiss MA, J Mol Biol. 2001 Jul 13;310(3):635-58. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11439029 11439029] | The dimerization domain of HNF-1alpha: structure and plasticity of an intertwined four-helix bundle with application to diabetes mellitus., Narayana N, Hua Q, Weiss MA, J Mol Biol. 2001 Jul 13;310(3):635-58. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11439029 11439029] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Hua, Q | + | [[Category: Hua, Q X.]] |
[[Category: Narayana, N.]] | [[Category: Narayana, N.]] | ||
| - | [[Category: Weiss, M | + | [[Category: Weiss, M A.]] |
[[Category: four-helix bundle]] | [[Category: four-helix bundle]] | ||
[[Category: non-canonical turn]] | [[Category: non-canonical turn]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:20:38 2008'' |
Revision as of 11:20, 21 February 2008
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Crystal Structure of Dimerization Domain (1-33) of HNF-1alpha
Overview
Maturity-onset diabetes mellitus of the young (MODY) is a human genetic syndrome most commonly due to mutations in hepatocyte nuclear factor-1alpha (HNF-1alpha). Here, we describe the crystal structure of the HNF-1alpha dimerization domain at 1.7 A resolution and assess its structural plasticity. The crystal's low solvent content (23%, v/v) leads to tight packing of peptides in the lattice. Two independent dimers, similar in structure, are formed in the unit cell by a 2-fold crystallographic symmetry axis. The dimers define a novel intertwined four-helix bundle (4HB). Each protomer contains two alpha-helices separated by a sharp non-canonical turn. Dimer-related alpha-helices form anti-parallel coiled-coils, including an N-terminal "mini-zipper" complementary in structure, symmetry and surface characteristics to transcriptional coactivator dimerization cofactor of HNF-1 (DCoH). A confluence of ten leucine side-chains (five per protomer) forms a hydrophobic core. Isotope-assisted NMR studies demonstrate that a similar intertwined dimer exists in solution. Comparison of structures obtained in multiple independent crystal forms indicates that the mini-zipper is a stable structural element, whereas the C-terminal alpha-helix can adopt a broad range of orientations. Segmental alignment of the mini-zipper (mean pairwise root-mean-square difference (rmsd) in C(alpha) coordinates of 0.29 A) is associated with a 2.1 A mean C(alpha) rmsd displacement of the C-terminal coiled-coil. The greatest C-terminal structural variation (4.1 A C(alpha) rmsd displacement) is observed in the DCoH-bound peptide. Diabetes-associated mutations perturb distinct structural features of the HNF-1alpha domain. One mutation (L12H) destabilizes the domain but preserves structural specificity. Adjoining H12 side-chains in a native-like dimer are predicted to alter the functional surface of the mini-zipper involved in DCoH recognition. The other mutation (G20R), by contrast, leads to a dimeric molten globule, as indicated by its 1H-NMR features and fluorescent binding of 1-anilino-8-naphthalene sulfonate. We propose that a glycine-specific turn configuration enables specific interactions between the mini-zipper and the C-terminal coiled-coil.
About this Structure
1JB6 is a Single protein structure of sequence from [1]. Full crystallographic information is available from OCA.
Reference
The dimerization domain of HNF-1alpha: structure and plasticity of an intertwined four-helix bundle with application to diabetes mellitus., Narayana N, Hua Q, Weiss MA, J Mol Biol. 2001 Jul 13;310(3):635-58. PMID:11439029
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