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PDBsum entry 1pcg
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protein ligands Protein-protein interface(s) links
Transcription/inhibitor PDB id
1pcg

 

 

 

 

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Contents
Protein chains
232 a.a. *
243 a.a. *
Ligands
LYS-DCY-ILE-LEU-
CYS-ARG-LEU-LEU-
GLN ×2
EST ×2
Waters ×1
* Residue conservation analysis
PDB id:
1pcg
Name: Transcription/inhibitor
Title: Helix-stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactions
Structure: Estrogen receptor. Chain: a, b. Fragment: ligand-binding domain. Synonym: er, estradiol receptor, er-alpha. Engineered: yes. Mutation: yes. Peptide inhibitor. Chain: e, f. Engineered: yes.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes
Biol. unit: Dimer (from PQS)
Resolution:
2.70Å     R-factor:   0.219     R-free:   0.254
Authors: A.M.Leduc,J.O.Trent,J.L.Wittliff,K.S.Bramlett,S.L.Briggs, N.Y.Chirgadze,Y.Wang,T.P.Burris,A.F.Spatola
Key ref:
A.M.Leduc et al. (2003). Helix-stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactions. Proc Natl Acad Sci U S A, 100, 11273-11278. PubMed id: 13679575 DOI: 10.1073/pnas.1934759100
Date:
16-May-03     Release date:   28-Oct-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P03372  (ESR1_HUMAN) -  Estrogen receptor from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		595 a.a.
232 a.a.*
Protein chain
Pfam   ArchSchema ?
P03372  (ESR1_HUMAN) -  Estrogen receptor from Homo sapiens
Seq:
Struc: 		 
Seq:
Struc: 		595 a.a.
243 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 6 residue positions (black crosses)

 

 
DOI no: 10.1073/pnas.1934759100 Proc Natl Acad Sci U S A 100:11273-11278 (2003)
PubMed id: 13679575  
 
 
Helix-stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactions.
A.M.Leduc, J.O.Trent, J.L.Wittliff, K.S.Bramlett, S.L.Briggs, N.Y.Chirgadze, Y.Wang, T.P.Burris, A.F.Spatola.
 
  ABSTRACT  
 
The interaction between nuclear receptors and coactivators provides an arena for testing whether protein-protein interactions may be inhibited by small molecule drug candidates. We provide evidence that a short cyclic peptide, containing a copy of the LXXLL nuclear receptor box pentapeptide, binds tightly and selectively to estrogen receptor alpha. Furthermore, as shown by x-ray analysis, the disulfide-bridged nonapeptide, nonhelical in aqueous solutions, is able to adopt a quasihelical conformer while binding to the groove created by ligand attachment to estrogen receptor alpha. An i, i+3 linked analog, H-Lys-cyclo(d-Cys-Ile-Leu-Cys)-Arg-Leu-Leu-Gln-NH2 (peptidomimetic estrogen receptor modulator 1), binds with a Ki of 25 nM, significantly better than an i, i+4 bridged cyclic amide, as predicted by molecular modeling design criteria. The induction of helical character, effective binding, and receptor selectivity exhibited by this peptide analog provide strong support for this strategy. The stabilization of minimalist surface motifs may prove useful for the control of other macromolecular assemblies, especially when an amphiphilic helix is crucial for the strong binding interaction between two proteins.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. X-ray structure of the LBD of ER associated with estradiol and PERM-1, depicting the induced helix formed by the disulfide bridged peptide when bound to the NR dimer LBD. The steroid ligand is shown in red, and the disulfide bridged peptide is shown in green. 		Figure 2.
Fig. 2. Interaction of PERM-1 with the LBD of ER .(A) Superposition of the structure ER /estradiol/PERM-1 (PDB ID 1PCG) with ER /DES/GRIP1 (PDB ID 3ERD [PDB] ) is viewed in the coactivator binding site. PERM-1 is colored by elements, whereas GRIP1 NR box II is in orange. The side chains of the two charge clamps in ER are displayed. (B) The molecular surface of ER shows a good fit between the hydrophobic residues of PERM-1 (green) and the coactivator binding cleft formed in estradiol bound ER (yellow). The surface formed by the charge clamps is colored in red and blue to indicate the orientation of the peptide anchored by polar interactions. The N-terminal lysine is positioned at the lower left, and the C-terminal glutamine amide is positioned at the upper right. The image was drawn with PYMOL (45).
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20882600 D.A.Guarracino, B.N.Bullock, and P.S.Arora (2011).
Protein-protein interactions in transcription: A fertile ground for helix mimetics.
  Biopolymers, 95, 1-7.  
20871934 T.Phan, H.D.Nguyen, H.Göksel, S.Möcklinghoff, and L.Brunsveld (2010).
Phage display selection of miniprotein binders of the Estrogen Receptor.
  Chem Commun (Camb), 46, 8207-8209.  
19724790 B.Vaz, S.Möcklinghoff, S.Folkertsma, S.Lusher, J.de Vlieg, and L.Brunsveld (2009).
Computational design, synthesis, and evaluation of miniproteins as androgen receptor coactivator mimics.
  Chem Commun (Camb), (), 5377-5379.  
19266524 J.A.Robinson (2009).
Design of protein-protein interaction inhibitors based on protein epitope mimetics.
  Chembiochem, 10, 971-973.  
19228693 K.Kato-Takagaki, Y.Mizukoshi, Y.Yoshizawa, D.Akazawa, Y.Torii, K.Ono, R.Tanimura, I.Shimada, and H.Takahashi (2009).
Structural and interaction analysis of glycoprotein VI-binding peptide selected from a phage display library.
  J Biol Chem, 284, 10720-10727.  
19767828 M.Aouida, A.Khodami-Pour, and D.Ramotar (2009).
Novel role for the Saccharomyces cerevisiae oligopeptide transporter Opt2 in drug detoxification.
  Biochem Cell Biol, 87, 653-661.  
19635407 M.Carraz, W.Zwart, T.Phan, R.Michalides, and L.Brunsveld (2009).
Perturbation of estrogen receptor alpha localization with synthetic nona-arginine LXXLL-peptide coactivator binding inhibitors.
  Chem Biol, 16, 702-711.  
19334772 P.S.Kutchukian, J.S.Yang, G.L.Verdine, and E.I.Shakhnovich (2009).
All-atom model for stabilization of alpha-helical structure in peptides by hydrocarbon staples.
  J Am Chem Soc, 131, 4622-4627.  
  18432312 D.Gallo, I.Haddad, G.Laurent, J.Vinh, F.Jacquemotte, Y.Jacquot, and G.Leclercq (2008).
Regulatory function of the P295-T311 motif of the estrogen receptor alpha - does proteasomal degradation of the receptor induce emergence of peptides implicated in estrogenic responses?
  Nucl Recept Signal, 6, e007.  
18374356 H.Zhang, Q.Zhao, S.Bhattacharya, A.A.Waheed, X.Tong, A.Hong, S.Heck, F.Curreli, M.Goger, D.Cowburn, E.O.Freed, and A.K.Debnath (2008).
A cell-penetrating helical peptide as a potential HIV-1 inhibitor.
  J Mol Biol, 378, 565-580.  
18793750 L.K.Henchey, A.L.Jochim, and P.S.Arora (2008).
Contemporary strategies for the stabilization of peptides in the alpha-helical conformation.
  Curr Opin Chem Biol, 12, 692-697.  
18464232 M.Seitz, L.T.Maillard, D.Obrecht, and J.A.Robinson (2008).
Molecular characterization of the NCoA-1-STAT 6 interaction.
  Chembiochem, 9, 1318-1322.  
17971985 J.Garner, and M.M.Harding (2007).
Design and synthesis of alpha-helical peptides and mimetics.
  Org Biomol Chem, 5, 3577-3585.  
17486549 K.Hamacher (2007).
Information theoretical measures to analyze trajectories in rational molecular design.
  J Comput Chem, 28, 2576-2580.  
17300979 V.Nahoum, and W.Bourguet (2007).
Androgen and estrogen receptors: potential of crystallography in the fight against cancer.
  Int J Biochem Cell Biol, 39, 1280-1287.  
17068076 D.Zhou, J.J.Ye, Y.Li, K.Lui, and S.Chen (2006).
The molecular basis of the interaction between the proline-rich SH3-binding motif of PNRC and estrogen receptor alpha.
  Nucleic Acids Res, 34, 5974-5986.  
16819755 H.D.Arndt (2006).
Small molecule modulators of transcription.
  Angew Chem Int Ed Engl, 45, 4552-4560.  
16674170 K.Hamacher, A.Hübsch, and J.A.McCammon (2006).
A minimal model for stabilization of biomolecules by hydrocarbon cross-linking.
  J Chem Phys, 124, 164907.  
16914190 P.Ascenzi, A.Bocedi, and M.Marino (2006).
Structure-function relationship of estrogen receptor alpha and beta: impact on human health.
  Mol Aspects Med, 27, 299-402.  
16622794 Y.Che, B.R.Brooks, and G.R.Marshall (2006).
Development of small molecules designed to modulate protein-protein interactions.
  J Comput Aided Mol Des, 20, 109-130.  
16782818 Y.Wang, N.Y.Chirgadze, S.L.Briggs, S.Khan, E.V.Jensen, and T.P.Burris (2006).
A second binding site for hydroxytamoxifen within the coactivator-binding groove of estrogen receptor beta.
  Proc Natl Acad Sci U S A, 103, 9908-9911.
PDB code: 2fsz
16222726 A.K.Galande, K.S.Bramlett, J.O.Trent, T.P.Burris, J.L.Wittliff, and A.F.Spatola (2005).
Potent inhibitors of LXXLL-based protein-protein interactions.
  Chembiochem, 6, 1991-1998.  
16122970 C.Y.Majmudar, and A.K.Mapp (2005).
Chemical approaches to transcriptional regulation.
  Curr Opin Chem Biol, 9, 467-474.  
16242379 S.Fletcher, and A.D.Hamilton (2005).
Protein surface recognition and proteomimetics: mimics of protein surface structure and function.
  Curr Opin Chem Biol, 9, 632-638.  
15049842 A.K.Galande, K.S.Bramlett, T.P.Burris, J.L.Wittliff, and A.F.Spatola (2004).
Thioether side chain cyclization for helical peptide formation: inhibitors of estrogen receptor-coactivator interactions.
  J Pept Res, 63, 297-302.  
15353804 L.D.Walensky, A.L.Kung, I.Escher, T.J.Malia, S.Barbuto, R.D.Wright, G.Wagner, G.L.Verdine, and S.J.Korsmeyer (2004).
Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix.
  Science, 305, 1466-1470.  
15049832 R.S.Savkur, and T.P.Burris (2004).
The coactivator LXXLL nuclear receptor recognition motif.
  J Pept Res, 63, 207-212.  
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.

 

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