High affinity Grb2-SH3 domain ligand incorporating Cβ-substituted prolines in a Sos-derived decapeptide

Jacquot, Yves; Broutin, Isabelle; Miclet, Emeric; Nicaise, Magali; Lequin, Olivier; Goasdoué, N.; Joss, Charlotte; Karoyan, Philippe; Desmadril, Michel; Ducruix, A.

doi:10.1016/j.bmc.2006.11.002

Cited by 24 publications

(26 citation statements)

References 22 publications

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“…Thus, we attempted to increase the binding affinity of PNRC‐D for Grb2 by exploring the effects of different peptide derivatives (longer peptides or dimers) appropriate for an efficient fitting on both Grb2‐SH3 domains …”

Section: Resultsmentioning

confidence: 99%

Identification of Polyproline II Regions Derived From the Proline‐Rich Nuclear Receptor Coactivators PNRC and PNRC2: New Insights for ERα Coactivator Interactions

et al. 2013

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Protein-protein interactions are crucial for signal transductions required for cell differentiation and proliferation. Their modulation is therefore key to the development of therapeutic alternatives, particularly in the context of cancer. According to literature data, the polyproline-rich nuclear receptor coactivators PNRC and PNRC2 interact with estrogen receptor (ERα) through their PxxP SH3-binding motifs. In a search to identify the molecular features governing this interaction, we explored using electronic circular dichroism (ECD) spectroscopy and molecular dynamics (MD) calculations, the capacity of a range of putative biologically active peptides derived from these proteins and containing this PxxP motif(s) to form polyproline II (PPII) domains. An additional more exhaustive structural study on a lead PPII peptide was also performed using 2D nuclear magnetic resonance (NMR) spectroscopy. With the exception of one of all the investigated peptides (PNRC-D), binding assays failed to detect any affinity for Grb2 SH3 domains, suggesting that PPII motifs issued from Grb2 antagonists have a binding mode distinct from those derived from Grb2 agonists. Instead, the peptides revealed a competitive binding ability against a synthetic peptide (ERα17p) with a putative PPII-cognate domain located within a coregulator recruitment region of ERα (AF-2 site). Our work, which constitutes the first structure-related interaction study concerning PNRC and PNRC2, supports not only the existence of PxxP-induced PPII sequences in these coregulators, but also confirms the presence of a PPII recognition site in the AF-2 of the steroid receptor ERα, a region important for transcription regulation.

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Section: Resultsmentioning

confidence: 99%

Identification of Polyproline II Regions Derived From the Proline‐Rich Nuclear Receptor Coactivators PNRC and PNRC2: New Insights for ERα Coactivator Interactions

et al. 2013

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“…15: G7-18NATE [53] ; 16: Phpr-pTyr-Leu, cis -3,4-methanoPro-Gln-NHBn [50] ; 17: Stattic [50,56] ; 18: SH3 binding inhibitor [59] ; 19: KAI-9803 [74] ; 20: ε V1-2/TAT; 21: An AKAP inhibitor, AKAP7 δ -L314E [88] .…”

Section: Figure 5 Protein Interaction Domain Binding Inhibitors Andmentioning

confidence: 99%

“…When this peptide was linked as a dimer by a connector containing two lysine residues, the affinity for Grb2 binding increased 400-fold to about 40 nM [58] . When the Val at position 5 was replaced by cis -C( β )-methyll -proline ( 18 , Figure 5 ) and dimerized, it yielded a 560-fold affinity enhancement, compared with the original sequence [59] .…”

Section: Figure 5 Protein Interaction Domain Binding Inhibitors Andmentioning

confidence: 99%

Non-ATP-competitive kinase inhibitors – enhancing selectivity through new inhibition strategies

Harrison¹,

Das²,

Karim³

et al. 2008

Expert Opinion on Drug Discovery

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“…For example, a PPII peptide issued from the nucleotide exchange factor Sos (VPPPVPPRRR, V10R) has been identified as a competitive inhibitor of the Grb2/Sos association by interacting with Grb2 SH3 domains with a mean Kd of 18 ± 1 µ M 36, 37. Accordingly, peptoid‐derived V10R mimetics38 and 3‐substituted prolines39 have been synthesized to antagonize the Grb2/Sos association which is implied, in certain cases, in the emergence of tumors.…”

Section: Introductionmentioning

confidence: 99%

Identification of a human estrogen receptor α‐derived antiestrogenic peptide that adopts a polyproline II conformation

Kapitán

Gallo

Goasdoué

et al. 2009

Journal of Peptide Science

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Polyproline II (PPII) helix is an extended secondary structure present in a number of proteins. PPII-containing sequences mediate specific protein-protein interactions with partners containing appropriate cognate domains called PPII-recognizing domains (PRDs) and are involved in the activation of intracellular signaling pathways. Thus, the identification of PPII structures in proteins is of great interest, not only to explore molecular and physiological mechanisms, but also to elaborate new potential drugs. By revisiting X-ray crystal structures of liganded alpha-type human estrogen receptor (ERalpha), we have identified an 11-residue PPII-helical sequence (D(321)AEPPILYSEY(331)) in the ligand-binding domain of the receptor. The data recorded by far-ultraviolet circular dichroism (far-UV CD), vibrational Raman optical activity (ROA) and differential scanning calorimetry (DSC) show that the corresponding peptide (Ac-DAEPPILYSEY-NH(2)) is particularly well structured in PPII, with the same proportion of PPII as observed from X-ray structures (approximately 85%). In addition, studies carried out on ERalpha-negative Evsa-T breast cancer cells transiently co-transfected with a pcDNA3-ERalpha plasmid and a Vit-tk-Luc reporter gene revealed that the peptide antagonizes the estradiol-induced transcription providing perspectives for researching new molecules with antagonistic properties.

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High affinity Grb2-SH3 domain ligand incorporating Cβ-substituted prolines in a Sos-derived decapeptide

Cited by 24 publications

References 22 publications

Identification of Polyproline II Regions Derived From the Proline‐Rich Nuclear Receptor Coactivators PNRC and PNRC2: New Insights for ERα Coactivator Interactions

Identification of Polyproline II Regions Derived From the Proline‐Rich Nuclear Receptor Coactivators PNRC and PNRC2: New Insights for ERα Coactivator Interactions

Non-ATP-competitive kinase inhibitors – enhancing selectivity through new inhibition strategies

Identification of a human estrogen receptor α‐derived antiestrogenic peptide that adopts a polyproline II conformation

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