Solution NMR Structure of the Helix-loop-Helix Domain of Human ID3 Protein, Northeast Structural Genomics Consortium Target HR3111A

Eletsky, A.; Wang, D.; Kohan, Eitan; Janjua, H.; Acton, T.B.; Xiao, Rong; Everett, J.K.; Montelione, G.T.; Szyperski, Thomas

doi:10.2210/pdb2lfh/pdb

2011

DOI: 10.2210/pdb2lfh/pdb

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Solution NMR Structure of the Helix-loop-Helix Domain of Human ID3 Protein, Northeast Structural Genomics Consortium Target HR3111A

A. Eletsky¹,

D. Wang²,

Eitan Kohan³

et al.

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Targeting of a Helix‐Loop‐Helix Transcriptional Regulator by a Short Helical Peptide

et al. 2017

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The Id proteins (Id1-4) are cell-cycle regulators that play a key role during development, in cancer and vascular disorders. They contain a conserved helix-loop-helix (HLH) domain that folds into a parallel four-helix bundle upon self- or hetero-association with basic-HLH transcription factors. By using such protein-protein interactions, the Id proteins inhibit cell differentiation and promote cell-cycle progression. Accordingly, their supporting role in cancer has been convincingly demonstrated, which makes these proteins interesting therapeutic targets. Herein we present a short peptide containing an (i,i+4)-lactam bridge and a hydrophobic (Φ) three-residue motif Φ(i)-Φ(i+3)-Φ(i+6), which adopts a helical conformation in water, shows Id protein binding in the low-micromolar range, penetrates into breast (MCF-7 and T47D) and bladder (T24) cancer cells, accumulates in the nucleus, and decreases cell viability to ∼50 %. Thus, this cyclopeptide is a promising scaffold for the development of Id protein binders that impair cancer cell viability.

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Targeting of a Helix‐Loop‐Helix Transcriptional Regulator by a Short Helical Peptide

et al. 2017

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Impact of the amino acid sequence on the conformation of side chain lactam‐bridged octapeptides

Neukirchen

Krieger

Roschger

et al. 2017

Journal of Peptide Science

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Synthetic helical peptides are valuable scaffolds for the development of modulators of protein-protein interactions involving helical motifs. Backbone-to-side chain or side chain-to-side chain constraints have been and still are intensively exploited to stabilize short α-helices. Very often, these constraints have been combined with backbone modifications induced by Cα-tetrasubstituted, β-, or γ-amino acids, which facilitate the α-peptide or α/β/γ-peptide adopting an α-helical conformation. In this work, we investigated the helical character of octapeptides that were cyclized by a Lys-Asp-(i,i + 4)-lactam bridge. We started with two sequences extracted from the helix-loop-helix region of the Id proteins, which are inhibitors of cell differentiation during development and in cancer. Nineteen analogs containing the lactam bridge at different positions and displaying different amino acid core triads (i + 1,2,3) as well as outer residues were prepared by solid-phase methodology. Their conformation in water and water/2,2,2-trifluoroethanol mixtures was investigated by circular dichroism (CD) spectroscopy. The cyclopeptides could be grouped in helix-prone and non-helix-prone structures. Both the amino acid core triad (i + 1,2,3) and the pendant residues positively or negatively affected the formation of a helical structure. Computational studies based on the NMR-derived helical structure of a cyclopeptide containing Aib at position (i + 2) of the triad were generally in agreement with the secondary structure propensity of the cyclopeptides observed by CD spectroscopy. In conclusion, the Lys-Asp-(i,i + 4)-lactam bridge may succeed or fail in the stabilization of short helices, depending on the primary structure. Moreover, computational methods may be valuable tools to discriminate helix-prone from non-helix-prone peptide-based macrolactams. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

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The Id-protein family in developmental and cancer-associated pathways

2017

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Inhibitors of DNA binding and cell differentiation (Id) proteins are members of the large family of the helix-loop-helix (HLH) transcription factors, but they lack any DNA-binding motif. During development, the Id proteins play a key role in the regulation of cell-cycle progression and cell differentiation by modulating different cell-cycle regulators both by direct and indirect mechanisms. Several Id-protein interacting partners have been identified thus far, which belong to structurally and functionally unrelated families, including, among others, the class I and II bHLH transcription factors, the retinoblastoma protein and related pocket proteins, the paired-box transcription factors, and the S5a subunit of the 26 S proteasome. Although the HLH domain of the Id proteins is involved in most of their protein-protein interaction events, additional motifs located in their N-terminal and C-terminal regions are required for the recognition of diverse protein partners. The ability of the Id proteins to interact with structurally different proteins is likely to arise from their conformational flexibility: indeed, these proteins contain intrinsically disordered regions that, in the case of the HLH region, undergo folding upon self- or heteroassociation. Besides their crucial role for cell-fate determination and cell-cycle progression during development, other important cellular events have been related to the Id-protein expression in a number of pathologies. Dysregulated Id-protein expression has been associated with tumor growth, vascularization, invasiveness, metastasis, chemoresistance and stemness, as well as with various developmental defects and diseases. Herein we provide an overview on the structural properties, mode of action, biological function and therapeutic potential of these regulatory proteins.

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Solution NMR Structure of the Helix-loop-Helix Domain of Human ID3 Protein, Northeast Structural Genomics Consortium Target HR3111A

Cited by 5 publications

References 0 publications

Targeting of a Helix‐Loop‐Helix Transcriptional Regulator by a Short Helical Peptide

Targeting of a Helix‐Loop‐Helix Transcriptional Regulator by a Short Helical Peptide

Impact of the amino acid sequence on the conformation of side chain lactam‐bridged octapeptides

The Id-protein family in developmental and cancer-associated pathways

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