PDBsum entry 1f93

Transcription

PDB id: 1f93

Contents

Protein chains

103 a.a. *

31 a.a. *

27 a.a. *

27 a.a. *

26 a.a. *

Waters ×62

* Residue conservation analysis

PDB id:

1f93

Name:

Transcription

Title:

Crystal structure of a complex between the dimerization domain of hnf- 1 alpha and the coactivator dcoh

Structure:

Dimerization cofactor of hepatocyte nuclear factor 1-alpha. Chain: a, b, c, d. Synonym: pterin-4-alpha-carbinolamine dehydratase, phs, dcoh. Engineered: yes. Hepatocyte nuclear factor 1-alpha. Chain: e, f, g, h. Fragment: dimerization domain (residues 1-32). Engineered: yes

Source:

Rattus norvegicus. Norway rat. Organism_taxid: 10116. Organ: liver. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: this peptide was chemically synthesized. The sequence of this peptide naturally occurs in mouse (mus musculus)

Biol. unit:

Tetramer (from PQS)

Resolution:

2.60Å R-factor: 0.257 R-free: 0.299

Authors:

R.B.Rose,J.H.Bayle,J.A.Endrizzi,J.D.Cronk,G.R.Crabtree,T.Alber

Key ref:

R.B.Rose et al. (2000). Structural basis of dimerization, coactivator recognition and MODY3 mutations in HNF-1alpha. Nat Struct Biol, 7, 744-748. PubMed id: 10966642 DOI: 10.1038/78966

Date:

06-Jul-00 Release date: 20-Sep-00

Protein chains

P61459  (PHS_RAT) -  Pterin-4-alpha-carbinolamine dehydratase from Rattus norvegicus

Seq: 104 a.a.

Struc: 103 a.a.

Protein chain

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

Seq: 628 a.a.

Struc: 31 a.a.

Protein chain

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

Seq: 628 a.a.

Struc: 27 a.a.

Protein chain

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

Seq: 628 a.a.

Struc: 27 a.a.

Protein chain

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

Seq: 628 a.a.

Struc: 26 a.a.

Enzyme reactions

• Enzyme class: Chains A, B, C, D: E.C.4.2.1.96 - 4a-hydroxytetrahydrobiopterin dehydratase.
• Pathway: Biopterin Biosynthesis
• Reaction: (4aS,6R)-4a-hydroxy-L-erythro-5,6,7,8-tetrahydrobiopterin = (6R)-L- erythro-6,7-dihydrobiopterin + H2O

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1038/78966

Nat Struct Biol 7:744-748 (2000)

PubMed id: 10966642

Structural basis of dimerization, coactivator recognition and MODY3 mutations in HNF-1alpha.

R.B.Rose, J.H.Bayle, J.A.Endrizzi, J.D.Cronk, G.R.Crabtree, T.Alber.

ABSTRACT

Maturity-onset diabetes of the young type 3 (MODY3) results from mutations in the transcriptional activator hepatocyte nuclear factor-1alpha (HNF-1alpha). Several MODY3 mutations target the HNF-1alpha dimerization domain (HNF-p1), which binds the coactivator, dimerization cofactor of HNF-1 (DCoH). To define the mechanism of coactivator recognition and the basis for the MODY3 phenotype, we determined the cocrystal structure of the DCoH-HNF-p1 complex and characterized biochemically the effects of MODY3 mutations in HNF-p1. The DCoH-HNF-p1 complex comprises a dimer of dimers in which HNF-p1 forms a unique four-helix bundle. Through rearrangements of interfacial side chains, a single, bifunctional interface in the DCoH dimer mediates both HNF-1alpha binding and formation of a competing, transcriptionally inactive DCoH homotetramer. Consistent with the structure, MODY3 mutations in HNF-p1 reduce activator function by two distinct mechanisms.

Selected figure(s)

Figure 1.
Figure 1. Stereo view of the experimental, MAD-phased 2.6 Å resolution, electron density map contoured at 1 superimposed on the refined model. Residues 8 -11 in helix 1 of HNF-p1 and the interacting amino acids of the DCoH dimer (residues 55 -57 and 43' -46', where primes denote residues in the neighboring subunit) are shown.

Figure 2.
Figure 2. Structure of the DCoH -HNF-p1 complex. a, The DCoH dimer (yellow and orange) binds the HNF-p1 dimer (light and dark blue) with two helix 2 sequences of DCoH in contact with two helix 1 sequences of HNF-p1. The two-fold rotation axes of the dimers coincide (arrow). b, The bound HNF-p1 dimer (light and dark blue) forms an antiparallel four-helix bundle. The view is along the two-fold rotation axis (+) with the DCoH binding surface in front. Seven Leu side chains in each monomer stabilize the dimer and make contacts with DCoH. Red spheres mark two residues mutated in MODY3 patients, Leu 12 and Gly 20. The site of a third MODY3 mutation, Gly 31, occurs in the disordered region of the chain beyond residue 30. c, Electrostatic potential displayed on the surface of the recognition helices of DCoH (red, <-2.5 kT/e; white, -2.5 to 2.5 kT/e; and blue, >2.5 kT/e). A stick representation of helix 1 of the HNF-p1 dimer (light blue) is superimposed on the surface. d, The corresponding electrostatic potential displayed on the surface of the HNF-1 recognition helices. A stick representation of the recognition helices of the bound DCoH (yellow) is superimposed. The two surfaces in (c) and (d) match through a 180° rotation about a central, vertical axis. Complementary positive (DCoH) and negative (HNF-p1) potentials are evident on the left and right edges of the two interfaces. e, Interactions between DCoH (yellow and orange) and HNF-p1 (light and dark blue), viewed along the DCoH helical axes. Only half of each helix is shown, because the interactions in the other half are identical. Hydrophobic residues forming the core of the interface are displayed in gray. Side chains within hydrogen bonding distance are connected by lines. DCoH Glu 58' caps the N-terminus of the HNF-p1 helix 1, the Leu 8 amide, and forms a hydrogen bond with Ser 6. DCOH Lys 59' forms a hydrogen bond to the C-terminus of the neighboring HNF-p1 helix, the carbonyl of Ser 19'.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Struct Biol (2000, 7, 744-748) copyright 2000.

Figures were selected by an automated process.