Quantitative analysis of cyclic β‐turn models

Perczel, A; Fasman, Gerald D.

doi:10.1002/pro.5560010310

Cited by 118 publications

(88 citation statements)

References 43 publications

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“…Studies of model compounds, mostly cyclic short peptides, have associated spectra exhibiting a minimum that is reminiscent of a red-shifted b-sheet spectrum with type-I b-turn conformations, but significant variability can be expected. 28,31,32 The assignment that we present is in accord with elements of subunit structure that are believed to be ordered in the 3.4 Å refined crystallographic structure of Head-II but disordered in the Prohead-II state.…”

Section: Circular Dichroism At Far-uv Wavelengthssupporting

confidence: 77%

Evidence that a Local Refolding Event Triggers Maturation of HK97 Bacteriophage Capsid

Lee

Gan

Tsuruta

et al. 2004

Journal of Molecular Biology

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Section: Circular Dichroism At Far-uv Wavelengthssupporting

confidence: 77%

Evidence that a Local Refolding Event Triggers Maturation of HK97 Bacteriophage Capsid

Lee

Gan

Tsuruta

et al. 2004

Journal of Molecular Biology

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“…S7) (49) point toward a role for secondary structure formation and hydrogen bonding in temperature-induced unfolded state collapse. Even though a contribution from ␣-helical conformations (23) and ␤ turns (61) should not be excluded, the contribution of ␤-structure formation may be particularly relevant. In kinetic synchrotron radiation CD experiments, we found earlier that collapsed unfolded CspTm exhibits a higher content of ␤ structure than the protein at high denaturant concentrations (16).…”

Section: Discussionmentioning

confidence: 99%

Single-molecule spectroscopy of the temperature-induced collapse of unfolded proteins

Nettels

Müller-Späth²,

Küster³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

214

252

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We used single-molecule FRET in combination with other biophysical methods and molecular simulations to investigate the effect of temperature on the dimensions of unfolded proteins. With singlemolecule FRET, this question can be addressed even under nearnative conditions, where most molecules are folded, allowing us to probe a wide range of denaturant concentrations and temperatures. We find a compaction of the unfolded state of a small cold shock protein with increasing temperature in both the presence and the absence of denaturant, with good agreement between the results from single-molecule FRET and dynamic light scattering. Although dissociation of denaturant from the polypeptide chain with increasing temperature accounts for part of the compaction, the results indicate an important role for additional temperaturedependent interactions within the unfolded chain. The observation of a collapse of a similar extent in the extremely hydrophilic, intrinsically disordered protein prothymosin ␣ suggests that the hydrophobic effect is not the sole source of the underlying interactions. Circular dichroism spectroscopy and replica exchange molecular dynamics simulations in explicit water show changes in secondary structure content with increasing temperature and suggest a contribution of intramolecular hydrogen bonding to unfolded state collapse.FRET ͉ polymer ͉ protein folding ͉ secondary structure ͉ chain dimensions T here is an increasing interest in the properties of unfolded proteins and their roles in the folding and cellular functions of proteins. A key motivation is that many proteins are marginally stable and only fold in the presence of their ligands or binding partners, opening new regulatory possibilities (1, 2). An important reason for recent progress is the growing availability of methods that provide structural information on these conformationally heterogeneous systems, such as NMR (3), scattering methods (4, 5), and single-molecule . Although NMR provides mostly local details, small-angle X-ray scattering (SAXS), dynamic light scattering (DLS), and single-molecule FRET provide overall hydrodynamic or long-range distance information. An important advantage of single-molecule FRET is the separation of folded and unfolded subpopulations (9). As a result, unfolded state properties can be investigated even in the presence of folded molecules (i.e., under near-native conditions, which are physiologically most relevant). This advance has led to the observation of a continuous collapse of the unfolded state with decreasing denaturant concentrations (10), a behavior that now has been demonstrated for a large number of proteins (11-18) and peptides (19). Recent advances in the application of theoretical models have led to a quantitative description of this unfolded state collapse in terms of polymerphysical concepts (15,(20)(21)(22)(23). Such chain compaction also has been demonstrated to result in increased internal friction and a slowdown of intramolecular dynamics of the polypeptide (19, 26), which can affect...

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“…[27][28][29] Due to the cyclic structure of investigated peptides, it is also possible that the shape of the curves is influenced by the presence of bent conformations. 30,31 Overall, it can be surmised that none of the peptides had significant secondary structure on their own, and that preformed peptide structure is not a likely cause of differential competition effects of the peptides. Likely, the peptides achieve a stabilized ordered structure only upon IL-5R␣ binding.…”

Section: Comparison Of Peptide Structural Propertiesmentioning

confidence: 99%

Cyclic peptide interleukin 5 antagonists mimic CD turn recognition epitope for receptor α

et al. 2004

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The cyclic peptide AF17121 (Ac-VDECWRIIASHTWFCAEE) that inhibits interleukin 5 (IL-5) function and IL-5 receptor alpha-chain (IL-5Ralpha) binding has been derived from recombinant random peptide library screening and follow-up synthetic variation. To better understand the structural basis of its antagonist activity, AF17121 and a series of analogs of the parent peptide were prepared by solid phase peptide synthesis. Sequence variation was focused on the charged residues Asp(2), Glu(3), Arg(6), Glu(17), and Glu(18). Two of those residues, Glu(3) and Arg(6), form an EXXR motif that was found to be common among library-derived IL-5 antagonists. The E and R in the EXXR motif have a proximity similar to charged residues in a previously identified receptor alpha binding region, the beta-strand between the C- and D-helices of human IL-5. Optical biosensor interaction kinetics and cell proliferation assays were used to evaluate the antagonist activities of the purified synthetic peptides, by measuring competition with the highly active single chain IL-5. Analogs in which acidic residues (Asp(2), Glu(3), Glu(17), and Glu(18)) were replaced individually by Ala retained substantial competition activity, with multiple replacements in these residues leading to fractional loss of potency at most. In contrast, R6A analogs had strongly reduced competition activity. The results reveal that the arginine residue is crucial for the IL-5Ralpha binding of AF17121, while the acidic residues are not essential though likely complex-stabilizing particularly in the Asp(2)-Glu(3) region. By CD, AF17121 exhibited mostly disordered structure with evidence for a small beta-sheet content, and replacement of the arginine had no influence on the observed secondary structure of the peptides. The dominance of Arg(6) in AF17121 activity corresponds to previous findings of dominance of the positive charge balance in the antiparallel beta-sheet of IL-5 composed of (88)EERRR(92) in one strand of the CD turn region of IL-5 and with Arg(32) in the neighboring beta-strand. These results argue that AF17121 and related library-derived peptides function by mimicking the CD turn receptor alpha recognition epitope in IL-5 and open the way to small molecule antagonist design.

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Quantitative analysis of cyclic β‐turn models

Cited by 118 publications

References 43 publications

Evidence that a Local Refolding Event Triggers Maturation of HK97 Bacteriophage Capsid

Evidence that a Local Refolding Event Triggers Maturation of HK97 Bacteriophage Capsid

Single-molecule spectroscopy of the temperature-induced collapse of unfolded proteins

Cyclic peptide interleukin 5 antagonists mimic CD turn recognition epitope for receptor α

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