Trapping a Folding Intermediate of the α-Helix: Stabilization of the π-Helix

Chapman, Ross; Kulp, John L.; Patgiri, Anupam; Kallenbach, Neville R.; Bracken, Clay; Arora, Paramjit S.

doi:10.1021/bi800136m

Cited by 32 publications

(30 citation statements)

References 44 publications

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“…Interestingly, the spectra have a minimum ellipticity at 206-208 significantly lower than the minimum at 222 nm. Similar spectra have been observed for KL 4 in DPPC:POPG LUVs [24] and peptides which are constrained to form π-helices in buffer [35]. Interpretation of the CD spectra in terms of helix content is complicated by the fact that SP-B 59-80 does not form a typical amphipathic α-helix when projected on a helical wheel.…”

Section: Resultssupporting

confidence: 57%

Interactions of the C-terminus of lung surfactant protein B with lipid bilayers are modulated by acyl chain saturation

Antharam

Farver

Kuznetsova

et al. 2008

Biochimica et Biophysica Acta (BBA) - Biomembranes

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Summary Lung surfactant protein B (SP-B) is critical to minimizing surface tension in the alveoli. The C-terminus of SP-B, residues 59-80, has much of the surface activity of the full protein and serves as a template for the development of synthetic surfactant replacements. The molecular mechanisms responsible for its ability to restore lung compliance were investigated with circular dichroism, differential scanning calorimetry, and 31P and 2H solid-state NMR spectroscopy. SP-B59-80 forms an amphipathic helix which alters lipid organization and acyl chain dynamics in fluid lamellar phase 4:1 DPPC:POPG and 3:1 POPC:POPG MLVs. At higher levels of SP-B59-80 in the POPC:POPG lipid system a transition to a nonlamellar phase is observed while DPPC:POPG mixtures remain in a lamellar phase. Deuterium NMR shows an increase in acyl chain order in DPPC:POPG MLVs on addition of SP-B59-80; in POPC:POPG MLVs, acyl chain order parameters decrease. Our results indicate SP-B59-80 penetrates deeply into DPPC:POPG bilayers and binds more peripherally to POPC:POPG bilayers. Similar behavior has been observed for KL4, a peptide mimetic of SP-B which was originally designed using SP-B59-80 as a template and has been clinically demonstrated to be successful in treating respiratory distress syndrome. The ability of these helical peptides to differentially partition into lipid lamellae containing varying levels of monounsaturation and subsequent changes in lipid dynamics suggest a mechanism for lipid organization and trafficking within the dynamic lung environment.

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Section: Resultssupporting

confidence: 57%

Interactions of the C-terminus of lung surfactant protein B with lipid bilayers are modulated by acyl chain saturation

Antharam

Farver

Kuznetsova

et al. 2008

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…RCM is known to provide mixtures of alkenyl E/Z geometric isomers during the methathesis reaction. Previously reported examples of RCM macrocyclizations performed on large peptide substrates have highlighted the difficulties of obtaining defined E/Z geometries at the ring-forming alkenyl junction 24–28. Consistent with these prior studies, our current work does not explicitly define the geometries of RCM ring closure, nor does it extrapolate conformations of the resulting macrocycles.…”

Section: Synthesismentioning

confidence: 53%

Application of ring-closing metathesis macrocyclization to the development of Tsg101-binding antagonists

Liu

Stephen

Waheed

et al. 2010

Bioorganic & Medicinal Chemistry Letters

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HIV-1 viral budding involves binding of the viral Gag p6 protein to the ubiquitin E2 variant domain of the human tumor susceptibility gene 101 protein (Tsg101). Recognition of p6 by Tsg101 is mediated in part by a proline-rich motif that contains the sequence "Pro-Thr-Ala-Pro" ("PTAP"). Using the p6-derived 9-mer sequence "PEPTAPPEE", we had previously improved peptide binding affinity by employing N-alkylglycine ("peptoid") residues. The current study applies ring-closing metathesis macrocyclization strategies to Tsg101-binding peptide-peptoid hybrids as an approach to stabilize binding conformations and to observe the effects of such macrocyclization on Tsg101-binding affinity and bioavailability. Viral release is a necessary component of HIV-1 replication. To be an efficient process, viral budding relies on recruitment of the ubiquitin E2 variant (UEV) domain of the human tumor susceptibility gene 101 protein (Tsg101) by major structural proteins of HIV-1.1 , 2 This entails the direct interaction of the Tsg101 UEV domain with a proline rich motif (PRM) within the viral Gag p6 protein that contains a conserved sequence, Pro-Thr/Ser-Ala-Pro ["P(T/S)AP"]. 3 , 4 Over-expression of the Tsg101 UEV inhibits virus release by interfering with processing of the p6 domains and this effect is abrogated by mutation within the P(T/S)AP binding site. In theory, blocking this critical Tsg101-p6 interaction could prevent viral budding and provide a basis for new targeted antiretroviral therapies.5 , 6 This is supported by the recent finding that inhibition of HIV budding can be achieved by cyclic peptides that interfere with Tsg101-Gag interactions.7In an effort to develop Tsg101-binding inhibitors using the reported p6-derived 9-mer wildtype (WT) sequence "P 1 E 2 P 3 T 4 A 5 P 6 P 7 E 8 E 9 ," we had previously improved Tsg101-binding affinity by applying hydrazone-and hydrazide-library techniques.8 We also reported an oxime-*Corresponding authors. liuf@ncifcrf.gov (F. Liu); tburke@helix.nih.gov (T.R. Burke).. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Supporting information Supporting information associated with this article, including reaction yields and analytical data for products 8a -8g, mass spectral data for peptides and peptide -peptoid hybrids and Tsg101 -binding affinities can be found, in the online version, at doi:10.1016/j.bmcl.2009.10.105. NIH Public Access Author ManuscriptBioorg Med Chem Lett. Author manuscript; available in PMC 2011 January 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript based post solid-phase diversification...

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“…31,32 Comparisons of experimental thermal denaturation curves with simulations of the Zimm–Bragg model 14–17 suggest that HBS helices are nucleated with the constant, σ, close to unity. 32–35 We have also demonstrated that HBS α-helices can target their cognate protein receptors with high affinity and specificity. 36–40 Significantly, the stabilized α-helices can modulate chosen intracellular protein-protein interactions while their unconstrained counterparts remain ineffective.…”

Section: Resultsmentioning

confidence: 91%

Nucleation Effects in Peptide Foldamers

2012

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Oligomers composed of β3-amino acid residues and a mixture of α- and β3-residues have emerged as proteolytically stable structural mimics of α-helices. An attractive feature of these oligomers is that they adopt defined conformations in short sequences. In this manuscript, we evaluate the impact of β3-residues as compared to their α-amino acid analogs in prenucleated helices. Our hydrogen-deuterium exchange results suggest that heterogeneous sequences composed of “αααβ” repeats are conformationally more rigid than the corresponding homogeneous α-peptide helices, with the macrocycle templating the helical conformation having a significant influence.

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Trapping a Folding Intermediate of the α-Helix: Stabilization of the π-Helix

Cited by 32 publications

References 44 publications

Interactions of the C-terminus of lung surfactant protein B with lipid bilayers are modulated by acyl chain saturation

Interactions of the C-terminus of lung surfactant protein B with lipid bilayers are modulated by acyl chain saturation

Application of ring-closing metathesis macrocyclization to the development of Tsg101-binding antagonists

Nucleation Effects in Peptide Foldamers

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