Update 1 of: Beta-Strand Mimetics

Loughlin, Wendy Anne; Tyndall, Joel D. A.; Glenn, M.; Hill, Timothy A.; Fairlie, David P.

doi:10.1021/cr900395y

Cited by 90 publications

(69 citation statements)

References 449 publications

(1,010 reference statements)

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“…Consistent with this model is the observation that certain HIV inhibitors that inhibit Ste24p are known to be ␤-strand mimetics (e.g. ritonavir) (54,55). Although Ste24p and M16A proteases can cleave common substrates in vitro (e.g.…”

Section: Discussionmentioning

confidence: 83%

Ste24p Mediates Proteolysis of Both Isoprenylated and Non-prenylated Oligopeptides

Hildebrandt

Arachea

Wiener

et al. 2016

Journal of Biological Chemistry

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Rce1p and Ste24p are integral membrane proteins involved in the proteolytic maturation of isoprenylated proteins. Extensive published evidence indicates that Rce1p requires the isoprenyl moiety as an important substrate determinant. By contrast, we report that Ste24p can cleave both isoprenylated and non-prenylated substrates in vitro, indicating that the isoprenyl moiety is not required for substrate recognition. Steady-state enzyme kinetics are significantly different for prenylated versus nonprenylated substrates, strongly suggestive of a role for substratemembrane interaction in protease function. Mass spectroscopy analyses identify a cleavage preference at bonds where P1 is aliphatic in both isoprenylated and non-prenylated substrates, although this is not necessarily predictive. The identified cleavage sites are not at a fixed distance position relative to the C terminus. In this study, the substrates cleaved by Ste24p are based on known isoprenylated proteins (i.e. K-Ras4b and the yeast a-factor mating pheromone) and non-prenylated biological peptides (A␤ and insulin chains) that are known substrates of the M16A family of soluble zinc-dependent metalloproteases. These results establish that the substrate profile of Ste24p is broader than anticipated, being more similar to that of the M16A protease family than that of the Rce1p CAAX protease with which it has been functionally associated.

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Section: Discussionmentioning

confidence: 83%

Ste24p Mediates Proteolysis of Both Isoprenylated and Non-prenylated Oligopeptides

Hildebrandt

Arachea

Wiener

et al. 2016

Journal of Biological Chemistry

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“…However, peptide bonds within secondary structure elements are poorly accessible to proteases due to the framework of stabilizing hydrogen bonds and steric hindrance, so that the proteolytic cleavage of antigens tends to occur in loop regions and surface exposed segments. In addition, most proteases bind their substrates in a fairly extended conformation, where side chains can favorably interact with the active site of the protease, requiring a certain degree of flexibility for optimal binding [24]. …”

Section: Discussionmentioning

confidence: 99%

“…Two of the Bet v 1 early cleavage sites are found in helices: Cleavage site I is located in the middle of the short helix α1, which forms part of the V-shaped support for the C-terminal part of helix α3, and cleavage site IV is located in the center of helix α3 (Figure 4). Protein helices are considered particularly poor substrates for proteolysis [24], since helices represent a fairly compressed structural motif with backbone amides being involved in an intramolecular pattern of hydrogen bonds. In helices, only the side chains are available for intermolecular interactions with a protease, and peptide bonds have to be transiently exposed to the surface to be available for proteolytic cleavage.…”

Section: Discussionmentioning

confidence: 99%

Conformational Flexibility Differentiates Naturally Occurring Bet v 1 Isoforms

Grutsch

Fuchs

Ahammer

et al. 2017

IJMS

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The protein Bet v 1 represents the main cause for allergic reactions to birch pollen in Europe and North America. Structurally homologous isoforms of Bet v 1 can have different properties regarding allergic sensitization and Th2 polarization, most likely due to differential susceptibility to proteolytic cleavage. Using NMR relaxation experiments and molecular dynamics simulations, we demonstrate that the initial proteolytic cleavage sites in two naturally occurring Bet v 1 isoforms, Bet v 1.0101 (Bet v 1a) and Bet v 1.0102 (Bet v 1d), are conformationally flexible. Inaccessible cleavage sites in helices and strands are highly flexible on the microsecond-millisecond time scale, whereas those located in loops display faster nanosecond-microsecond flexibility. The data consistently show that Bet v 1.0102 is more flexible and conformationally heterogeneous than Bet v 1.0101. Moreover, NMR hydrogen-deuterium exchange measurements reveal that the backbone amides in Bet v 1.0102 are significantly more solvent exposed, in agreement with this isoform’s higher susceptibility to proteolytic cleavage. The differential conformational flexibility of Bet v 1 isoforms, along with the transient exposure of inaccessible sites to the protein surface, may be linked to proteolytic susceptibility, representing a potential structure-based rationale for the observed differences in Th2 polarization and allergic sensitization.

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“…[74] Linear and cyclic trimer oligomers of (S)-valine-derived thiazole units 5 (R = i-Pr, Scheme 1) exhibited low micromolar inhibition of human p-glycoprotein. Consistent with being effective amide bond replacements, thiazole-based amino acids have also been used to construct peptide secondary structure analogous to those of natural amino acids, such as helical oligomers, [70,75] b-strand mimics, [72] and turn mimics [69,71].…”

Section: Thiazoles As Amide Bond Replacementsmentioning

confidence: 99%