PDBsum entry: 1a52

Receptor

PDB id: 1a52

Contents

Protein chains

239 a.a. *

Ligands

EST ×2

Metals

_AU ×6

Waters ×30

* Residue conservation analysis

PDB id:

1a52

Name:

Receptor

Title:

Estrogen receptor alpha ligand-binding domain complexed to e

Structure:

Estrogen receptor. Chain: a, b. Fragment: ligand-binding domain. Synonym: erlbd. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Cell_line: bl21. Gene: esr. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Dimer (from PDB file)

Resolution:

2.80Å R-factor: 0.223 R-free: 0.274

Authors:

D.M.Tanenbaum,Y.Wang,P.B.Sigler

Key ref:

D.M.Tanenbaum et al. (1998). Crystallographic comparison of the estrogen and progesterone receptor's ligand binding domains. Proc Natl Acad Sci U S A, 95, 5998-6003. PubMed id: 9600906 DOI: 10.1073/pnas.95.11.5998

Date:

19-Feb-98 Release date: 16-Sep-98

Protein chains

P03372  (ESR1_HUMAN) -  Estrogen receptor

Seq: 595 a.a.

Struc: 239 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

 Gene Ontology (GO) functional annotation 

• Cellular component: nucleus (1 term)
• Biological process: steroid hormone mediated signaling pathway (2 terms)
• Biochemical function: DNA binding (3 terms)

DOI no: 10.1073/pnas.95.11.5998

Proc Natl Acad Sci U S A 95:5998-6003 (1998)

PubMed id: 9600906

Crystallographic comparison of the estrogen and progesterone receptor's ligand binding domains.

D.M.Tanenbaum, Y.Wang, S.P.Williams, P.B.Sigler.

ABSTRACT

The 2.8-A crystal structure of the complex formed by estradiol and the human estrogen receptor-alpha ligand binding domain (hERalphaLBD) is described and compared with the recently reported structure of the progesterone complex of the human progesterone receptor ligand binding domain, as well as with similar structures of steroid/nuclear receptor LBDs solved elsewhere. The hormone-bound hERalphaLBD forms a distinctly different and probably more physiologically important dimer interface than its progesterone counterpart. A comparison of the specificity determinants of hormone binding reveals a common structural theme of mutually supported van der Waals and hydrogen-bonded interactions involving highly conserved residues. The previously suggested mechanism by which the estrogen receptor distinguishes estradiol's unique 3-hydroxy group from the 3-keto function of most other steroids is now described in atomic detail. Mapping of mutagenesis results points to a coactivator-binding surface that includes the region around the "signature sequence" as well as helix 12, where the ligand-dependent conformation of the activation function 2 core is similar in all previously solved steroid/nuclear receptor LBDs. A peculiar crystal packing event displaces helix 12 in the hERalphaLBD reported here, suggesting a higher degree of dynamic variability than expected for this critical substructure.

Selected figure(s)

Figure 2.
Fig. 2. Arrangement of hER LBDs in the crystal structure. (A) The tetramer formed by the intermolecular disulfide bonds between Cys-530 of neighboring hER LBD molecules and dimerization around the local dyad. (Inset) A schematization of the arrangement. Positions of the disulfides are marked with a yellow disc with red "S." Red symbols in the center of the tetramer and schematic show the crystallographic dyad, and the red arrow in the inset indicates the noncrystallographic symmetry dyad. (B) Comparison of the dimers of holo-hER LBD, apo-hRXR LBD, and holo-hPRLBD viewed down the local dyad (17, 18). The dimer interfaces of holo-hER LBD and apo-hRXR LBD are similar, with helices 7-10 as the major contributors. The holo-hPRLBD dimer interface is substantially different, composed predominantly of helices 11 and 12, as well as the extreme C-terminal tail. Drawn with RIBBONS (29).

Figure 3.
Fig. 3. Specificity determinants of the hormone-binding site specifies 3-hydroxy vs. 3-keto steroids. (A) The hydrogen-bonding network as seen in the hER LBD and hPRLBD (18). The discriminating relationship of Glu/Gln to the 3-hydroxy/keto of the steroid is supported by a network of water-mediated hydrogen bonds involving the side chain of a conserved Arg and backbone carbonyl of a conserved Phe that, in turn, are fixed by hydrophobic contacts with the steroid ring. Note that the PR has no obvious hydrogen bonding discrimination at the 20-keto position of progesterone comparable to the hydrogen-bonding interaction seen between the 17-hydroxyl of estradiol and His-524. (B) Space-filling representation of estradiol in the ligand-binding pocket of hER LBD and progesterone in the ligand-binding pocket of hPRLBD (18). For the proteins, carbon atoms are gray, oxygen atoms red, sulfur atoms yellow and nitrogen atoms blue. For the hormones, carbon atoms are cyan, oxygen atoms magenta. Drawn with MIDAS (36). (C) Schematic of estradiol in the hER LBD ligand-binding pocket in the structure shown here; hormone (red) rings are lettered, and carbon atoms are numbered. Residues hydrogen bonded directly to the hormone are blue. Dashed lines indicate hydrophobic van der Waals contacts with the hormone. Residues conserved among the steroid receptors are green, and variable residues are black. Residues contributed by helix 12 (1) are not shown.

Figures were selected by an automated process.