PDBsum entry: 1kb6

Transcription/DNA

PDB-id

1kb6

	Biological unit* = asymmetric unit, as shown (as deduced by PQS*)


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Description

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Protein chains

DNA/RNA

Metal ions

_ZN ×4

Waters ×34

* Residue conservation analysis

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PDB id:

1kb6

Name:

Transcription/DNA

Title:

Crystal structure of vdr DNA-binding domain bound to rat osteocalcin (oc) response element

Structure:

5'- d( Cp Ap Cp Gp Gp Gp Tp Gp Ap Ap Tp Gp Ap Gp Gp Ap Cp A)- 3'. Chain: c. Engineered: yes. Other_details: rat osteocalcin (oc) response element. 5'- d( Tp Gp Tp Cp Cp Tp Cp Ap Tp Tp Cp Ap Cp Cp Cp Gp Tp G)- 3'.

Source:

Synthetic: yes. Homo sapiens. Human. Organism_taxid: 9606. Gene: vdr. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Biological unit:

Tetramer (from PQS)

UniProt:

Chain A: P11473 (VDR_HUMAN)

Seq:

Struc:


Seq:				427 a.a.

Struc:				94 a.a.

Chain B: P11473 (VDR_HUMAN)

Seq:

Struc:

Seq:

427 a.a.

Struc:

101 a.a.

Key:		PfamA domain
		Secondary structure			CATH domain

Resolution:

2.70Å

R-factor:

0.223

R-free:

0.275

Authors:

P.L.Shaffer,D.T.Gewirth

Key ref:

P.L.Shaffer and D.T.Gewirth (2002). Structural basis of VDR-DNA interactions on direct repeat response elements.. EMBO J, 21, 2242-2252. [PubMed id: 11980721] [DOI: 10.1093/emboj/21.9.2242]

Date:

05-Nov-01

Release date:

03-May-02

Related entries:

1kb2
crystal structure of vdr DNA-binding domain bound to mouse
osteopontin (spp) response element
1kb4
crystal structure of vdr DNA-binding domain bound to a
canonical direct repeat with three base pair spacer (dr3)
response element

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Key reference

DOI no: 10.1093/emboj/21.9.2242 EMBO J 21:2242-2252 (2002)

PubMed id: 11980721

Structural basis of VDR-DNA interactions on direct repeat response elements.

P.L.Shaffer, D.T.Gewirth.

ABSTRACT

The vitamin D receptor (VDR) forms homo- or heterodimers on response elements composed of two hexameric half-sites separated by 3 bp of spacer DNA. We describe here the crystal structures at 2.7-2.8 A resolution of the VDR DNA-binding region (DBD) in complex with response elements from three different promoters: osteopontin (SPP), canonical DR3 and osteocalcin (OC). These structures reveal the chemical basis for the increased affinity of VDR for the SPP response element, and for the poor stability of the VDR-OC complex, relative to the canonical DR3 response element. The homodimeric protein-protein interface is stabilized by van der Waals interactions and is predominantly non-polar. An extensive alpha-helix at the C-terminal end of the VDR DBD resembles that found in the thyroid hormone receptor (TR), and suggests a mechanism by which VDR and TR discriminate among response elements. Selective structure-based mutations in the asymmetric homodimeric interface result in a VDR DBD protein that is defective in homodimerization but now forms heterodimers with the 9-cis retinoic acid receptor (RXR) DBD.

Selected figure(s)

Figure 1.
Figure 1 Protein and DNA constructs used in the structure determination. (A) The human VDR DBD. Sequence numbers are for full-length hVDR and those in parentheses refer to the common hormone receptor DBD numbering scheme. Residues in italics are disordered in all of the structures. (B) The 18 bp DNA duplexes used in co-crystallization, shown 5' arrow 3' in the top strand. Half-sites are shown in boxes and are numbered by base pair. The DR3 sequence contains a direct repeat of two consensus half-sites. SPP is the mouse osteopontin VDRE and OC is the rat osteocalcin VDRE. Bases that differ from the consensus sequence are shaded gray and the structurally significant changes are highlighted in black. Estimates of relative binding of VDR DBD homodimers to each sequence are also shown. Figure 3.
Figure 3 Experimental electron density and homodimeric assembly. (A) Unbiased experimental electron density from SAD phases. The map is contoured around the CTE of the upstream subunit of the VDR DBD−DR3 structure, which is shown as a C[ ]trace. (B) A portion of the 2F[o] = F[c] electron density map showing intersubunit dimerization contacts. (C) Stereo view of the dimerization interface in a van der Waals surface representation. (A) and (B) were made with Xtalview (McRee, 1999), and (C) was prepared with Ribbons.

The above figures are reprinted from an Open Access publication published by Macmillan Publishers Ltd: EMBO J (2002, 21, 2242-2252) copyright 2002.

Figures were selected by the author.

Literature references that cite this PDB file's key reference

PubMed id Reference

18612376 F.Claessens, S.Denayer, N.Van Tilborgh, S.Kerkhofs, C.Helsen, and A.Haelens (2008).
Diverse roles of androgen receptor (AR) domains in AR-mediated signaling.

Nucl Recept Signal, 6, e008.

18829458 P.Lu, G.B.Rha, M.Melikishvili, G.Wu, B.C.Adkins, M.G.Fried, and Y.I.Chi (2008).
Structural Basis of Natural Promoter Recognition by a Unique Nuclear Receptor, HNF4{alpha}: DIABETES GENE PRODUCT.

J Biol Chem, 283, 33685-33697.

PDB code: 3cbb

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.

17307735 K.Saavalainen, M.I.Tammi, T.Bowen, M.L.Schmitz, and C.Carlberg (2007).
Integration of the activation of the human hyaluronan synthase 2 gene promoter by common cofactors of the transcription factors retinoic acid receptor and nuclear factor kappaB.

J Biol Chem, 282, 11530-11539.

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

17014620 M.Wjst (2006).
The vitamin D slant on allergy.

Pediatr Allergy Immunol, 17, 477-483.

16085755 J.E.Donald, and E.I.Shakhnovich (2005).
Predicting specificity-determining residues in two large eukaryotic transcription factor families.

Nucleic Acids Res, 33, 4455-4465.

15722343 K.Saavalainen, S.Pasonen-Seppänen, T.W.Dunlop, R.Tammi, M.I.Tammi, and C.Carlberg (2005).
The human hyaluronan synthase 2 gene is a primary retinoic acid and epidermal growth factor responding gene.

J Biol Chem, 280, 14636-14644.

16204233 R.Yasmin, R.M.Williams, M.Xu, and N.Noy (2005).
Nuclear import of the retinoid X receptor, the vitamin D receptor, and their mutual heterodimer.

J Biol Chem, 280, 40152-40160.

15037741 P.L.Shaffer, A.Jivan, D.E.Dollins, F.Claessens, and D.T.Gewirth (2004).
Structural basis of androgen receptor binding to selective androgen response elements.

Proc Natl Acad Sci U S A, 101, 4758-4763.

PDB code: 1r4i

14739282 V.S.Melvin, C.Harrell, J.S.Adelman, W.L.Kraus, M.Churchill, and D.P.Edwards (2004).
The role of the C-terminal extension (CTE) of the estrogen receptor alpha and beta DNA binding domain in DNA binding and interaction with HMGB.

J Biol Chem, 279, 14763-14771.

14592980 S.Devarakonda, J.M.Harp, Y.Kim, A.Ozyhar, and F.Rastinejad (2003).
Structure of the heterodimeric ecdysone receptor DNA-binding complex.

EMBO J, 22, 5827-5840.

PDB codes: 1r0n 1r0o

12107189 G.Verrijdt, K.Schauwaers, A.Haelens, W.Rombauts, and F.Claessens (2002).
Functional interplay between two response elements with distinct binding characteristics dictates androgen specificity of the mouse sex-limited protein enhancer.

J Biol Chem, 277, 35191-35201.

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.