PDBsum entry 1jb6

Transcription

PDB id: 1jb6

Contents

Protein chains

33 a.a.

28 a.a.

Waters ×55

PDB id:

1jb6

Name:

Transcription

Title:

Crystal structure of dimerization domain (1-33) of hnf-1alpha

Structure:

Hepatocyte nuclear factor 1-alpha. Chain: a, b. Fragment: dimerization domain (residues 1-32). Synonym: hnf-1a. Engineered: yes

Source:

Synthetic: yes. Other_details: this peptide was chemically synthesized. The sequence of this peptide occurs naturally in mus musculus (mouse) as well as in homo sapiens (humans).

Biol. unit:

Not given

Resolution:

1.70Å R-factor: 0.231 R-free: 0.245

Authors:

N.Narayana,Q.-X.Hua,M.A.Weiss

Key ref:

N.Narayana et al. (2001). The dimerization domain of HNF-1alpha: structure and plasticity of an intertwined four-helix bundle with application to diabetes mellitus. J Mol Biol, 310, 635-658. PubMed id: 11439029 DOI: 10.1006/jmbi.2001.4780

Date:

01-Jun-01 Release date: 11-Jul-01

Protein chain

P22361  (HNF1A_MOUSE) -  Hepatocyte nuclear factor 1-alpha from Mus musculus

Seq: 628 a.a.

Struc: 33 a.a.*

Protein chain

P22361  (HNF1A_MOUSE) -  Hepatocyte nuclear factor 1-alpha from Mus musculus

Seq: 628 a.a.

Struc: 28 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

DOI no: 10.1006/jmbi.2001.4780

J Mol Biol 310:635-658 (2001)

PubMed id: 11439029

The dimerization domain of HNF-1alpha: structure and plasticity of an intertwined four-helix bundle with application to diabetes mellitus.

N.Narayana, Q.Hua, M.A.Weiss.

ABSTRACT

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.

Selected figure(s)

Figure 2.
Figure 2. Leucine-rich cluster in HNF-p1w dimer. (a) and (b) Ribbon representations (related by 180° about the horizontal axis passing between L12 and L26, and L12' and L26') of the HNF-p1w dimer. CPK models of leucine side-chains that form the leucine-rich cluster in core. In one protomer, the ribbon is shown in black and the leucine residues in red (L12, MSe13, L16, L21, L26). In the other protomer, the ribbon is colored gray and leucine side-chains green (L12', MSe13', L16', L21', L26'). Each protomer contributes four leucine and one selenomethionine residue. (c) A stereo view of the leucine-rich cluster shown in (a).

Figure 10.
Figure 10. Surface representation of HNF-p1w dimer and L12H homology model. (a) Electrostatic potential of the DCoH-binding surface of HNF-p1w (stereo pair). The coloring code is red, < -10 kT/e; white, -10kT/e to 10kT/e; and blue, >10kT/e. Residues E11 and E18 are involved in ion-pair interactions with DCoH residues.[35] The exposed concave surface is complementary in shape to the top of the DCoH saddle as predicted by model building studies (see the text) and observed in the recent co-crystal structure. [35] (b) The DCoH-binding surface of HNF-p1w dimer has a leucine-rich stripe (leucine residues 5, 8, 12, 13, 16 and 21, and their symmetry-related residues) shown in green. The orientation of molecular surface (white) of the HNF-p1w dimer is same as in (a). L12 is located in the middle of the leucine-rich stripe. Residues 1-4 and 1'-4' have been omitted for clarity. (c)-(e) Homology model of the L12H variant dimer. (c) The variant side-chain is compatible with a native overall main-chain fold. One protomer is shown in cyan and the other in red; terminal residues 1-4 and 1'-4' are disordered in accord with NMR evidence of flexibility. (d) The structure of the mini-zipper is predicted to accommodate a pair of histidine side-chains (yellow) with exposure of polar N epsilon ring protons. Neighboring side-chains are in positions similar to those in crystal structure. (e) The surface of the variant mini-zipper is predicted to contain a weakly polar protuberance (yellow) due to the edges of the two His side-chains. This change in surface character would be expected to perturb DCoH binding. (a), (b) and (e) Generated using the program GRASP;[85] (c) and (d) (and other Figures) were made using InsightII (MSI, Inc., San Diego).

The above figures are reprinted by permission from Elsevier: J Mol Biol (2001, 310, 635-658) copyright 2001.

Figures were selected by an automated process.