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PDBsum entry 2a66

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protein dna_rna ligands metals links
Transcription/DNA PDB id
2a66
Jmol
Contents
Protein chain
95 a.a. *
DNA/RNA
Ligands
ACT
Metals
_ZN ×2
Waters ×86
* Residue conservation analysis
PDB id:
2a66
Name: Transcription/DNA
Title: Human liver receptor homologue DNA-binding domain (hlrh-1 dbd) in complex with dsdna from the hcyp7a1 promoter
Structure: 5'-d( Gp Tp Tp Cp Ap Ap Gp Gp Cp Cp Ap G)-3'. Chain: b. 5'-d( Cp Tp Gp Gp Cp Cp Tp Tp Gp Ap Ap C)-3'. Chain: c. Orphan nuclear receptor nr5a2. Chain: a. Fragment: residues 79-187, nr c4-type. Synonym: alpha-1-fetoprotein transcription factor, hepatocytic transcription factor, b1-binding factor, hb1f,
Source: Homo sapiens. Human. Organism_taxid: 9606. Other_details: synthesized oligonucleotide based on cyp7a1 gene promoter. Gene: nr5a2, b1f, cpf, ftf. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Trimer (from PQS)
Resolution:
2.20Å     R-factor:   0.196     R-free:   0.226
Authors: I.H.Solomon,J.M.Hager,R.Safi,D.P.Mcdonnell,M.R.Redinbo, E.A.Ortlund
Key ref:
I.H.Solomon et al. (2005). Crystal structure of the human LRH-1 DBD-DNA complex reveals Ftz-F1 domain positioning is required for receptor activity. J Mol Biol, 354, 1091-1102. PubMed id: 16289203 DOI: 10.1016/j.jmb.2005.10.009
Date:
01-Jul-05     Release date:   06-Dec-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
O00482  (NR5A2_HUMAN) -  Nuclear receptor subfamily 5 group A member 2
Seq:
Struc:
 
Seq:
Struc:
541 a.a.
95 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   1 term 
  Biological process     regulation of transcription, DNA-dependent   1 term 
  Biochemical function     DNA binding     5 terms  

 

 
DOI no: 10.1016/j.jmb.2005.10.009 J Mol Biol 354:1091-1102 (2005)
PubMed id: 16289203  
 
 
Crystal structure of the human LRH-1 DBD-DNA complex reveals Ftz-F1 domain positioning is required for receptor activity.
I.H.Solomon, J.M.Hager, R.Safi, D.P.McDonnell, M.R.Redinbo, E.A.Ortlund.
 
  ABSTRACT  
 
The DNA-binding and ligand-binding functions of nuclear receptors are localized to independent domains separated by a flexible hinge. The DNA-binding domain (DBD) of the human liver receptor homologue-1 (hLRH-1), which controls genes central to development and metabolic homeostasis, interacts with monomeric DNA response elements and contains an Ftz-F1 motif that is unique to the NR5A nuclear receptor subfamily. Here, we present the 2.2A resolution crystal structure of the hLRH-1 DBD in complex with duplex DNA, and elucidate the sequence-specific DNA contacts essential for the ability of LRH-1 to bind to DNA as a monomer. We show that the unique Ftz-F1 domain folds into a novel helix that packs against the DBD but does not contact DNA. Mutations expected to disrupt the positioning of the Ftz-F1 helix do not eliminate DNA binding but reduce the transcriptional activity of full-length LRH-1 significantly. Moreover, we find that altering the Ftz-F1 helix positioning eliminates the enhancement of LRH-1-mediated transcription by the coactivator GRIP1, an action that is associated primarily with the distantly located ligand-binding domain (LBD). Taken together, these results indicate that subtle structural changes in a nuclear receptor DBD can exert long-range functional effects on the LBD of a receptor, and significantly impact transcriptional regulation.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Crystal structure of the hLRH-1 DBD-DNA complex. (a) Sequence and domain structure of the hLRH-1 DBD. (b) Structure of the hLRH-1 DBD-DNA complex, with the core DBD, CTE, and Ftz-F1 domains rendered in brown, yellow, and olive, respectively. The DNA bases in the 5'-TCA extension are in cyan and magenta. (c) Stereoview of the simulated annealing F[o] -F[c] omit map electron density (2.2 Å resolution, contoured at 1s) for the DNA bases in the 5'-extension.
Figure 2.
Figure 2. hLRH-1 DBD-DNA contacts. (a) Schematic view of protein-DNA interactions. Boxed protein residues make direct DNA contacts, while non-boxed residues form water-mediated interactions (with water molecules indicated as red spheres). Protein and DNA colors are as in Figure 1(b). Arrows point from hydrogen bond donors to acceptors. (b) Stereoview of the sequence-specific interactions formed between the DBD CTE and the 5'-TCA extension. Hydrogen bonds are indicated.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2005, 354, 1091-1102) copyright 2005.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20607599 P.T.Thiruchelvam, C.F.Lai, H.Hua, R.S.Thomas, A.Hurtado, W.Hudson, A.R.Bayly, F.J.Kyle, M.Periyasamy, A.Photiou, A.C.Spivey, E.A.Ortlund, R.J.Whitby, J.S.Carroll, R.C.Coombes, L.Buluwela, and S.Ali (2011).
The liver receptor homolog-1 regulates estrogen receptor expression in breast cancer cells.
  Breast Cancer Res Treat, 127, 385-396.  
20096661 J.C.Heng, B.Feng, J.Han, J.Jiang, P.Kraus, J.H.Ng, Y.L.Orlov, M.Huss, L.Yang, T.Lufkin, B.Lim, and H.H.Ng (2010).
The nuclear receptor Nr5a2 can replace Oct4 in the reprogramming of murine somatic cells to pluripotent cells.
  Cell Stem Cell, 6, 167-174.  
19015525 E.P.Sablin, A.Woods, I.N.Krylova, P.Hwang, H.A.Ingraham, and R.J.Fletterick (2008).
The structure of corepressor Dax-1 bound to its target nuclear receptor LRH-1.
  Proc Natl Acad Sci U S A, 105, 18390-18395.
PDB code: 3f5c
18838537 L.A.Campbell, E.J.Faivre, M.D.Show, J.G.Ingraham, J.Flinders, J.D.Gross, and H.A.Ingraham (2008).
Decreased recognition of SUMO-sensitive target genes following modification of SF-1 (NR5A1).
  Mol Cell Biol, 28, 7476-7486.  
18474528 S.C.Roemer, J.Adelman, M.E.Churchill, and D.P.Edwards (2008).
Mechanism of high-mobility group protein B enhancement of progesterone receptor sequence-specific DNA binding.
  Nucleic Acids Res, 36, 3655-3666.  
17426125 M.Jakób, R.Kołodziejczyk, M.Orłowski, S.Krzywda, A.Kowalska, J.Dutko-Gwóźdź, T.Gwóźdź, M.Kochman, M.Jaskólski, and A.Ozyhar (2007).
Novel DNA-binding element within the C-terminal extension of the nuclear receptor DNA-binding domain.
  Nucleic Acids Res, 35, 2705-2718.
PDB code: 2han
17140726 T.F.Lerch, M.Xu, T.S.Jardetzky, K.E.Mayo, I.Radhakrishnan, R.Kazer, L.D.Shea, and T.K.Woodruff (2007).
The structures that underlie normal reproductive function.
  Mol Cell Endocrinol, 267, 1-5.  
16931575 S.C.Roemer, D.C.Donham, L.Sherman, V.H.Pon, D.P.Edwards, and M.E.Churchill (2006).
Structure of the progesterone receptor-deoxyribonucleic acid complex: novel interactions required for binding to half-site response elements.
  Mol Endocrinol, 20, 3042-3052.
PDB code: 2c7a
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.