Hormone-receptor interactions: a study of the binding of hormone-substituted tobacco mosaic virus to membrane vesicles by dynamic light scattering and by transient electric bi-refringence

Schwyzer, R.; Kriwaczek, V. M.; Baumann, Kurt; Haller, Hans R.; Wider, Gerhard; Wiltzius, Pierre

doi:10.1351/pac197951040831

Cited by 8 publications

(2 citation statements)

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“…The third model of protein interaction involves a natively unstructured protein that folds upon interaction with another partner. This was proposed for peptide hormones in the 1970s by Robert Schwyzer ( Schwyzer et al., 1979 ) and experimentally exemplified by X-ray analysis and NMR studies of glucagon in the Blundell and Wüttrich labs ( Braun et al., 1983 , Sasaki et al., 1975 ) suggesting a disorder-to-order transition on receptor binding from glucagon with a single turn of helix in solution by NMR ( Braun et al, 1983 ) to one with a much longer region defined by X-ray analysis in the trimer ( Sasaki et al, 1975 ) and at lipid interfaces ( Braun et al, 1983 ) and proposed at the receptor ( Blundell, 1979 , Blundell and Wood, 1982 ). Subsequently, Wright & Dyson ( Wright and Dyson, 1999 , Wright and Dyson, 2009 ) showed that such concerted folding and binding involving peptides or disordered regions of polypeptide chains is actually widespread in intracellular regulatory systems.…”

Section: Flexibility In Partner Interactionsmentioning

confidence: 97%

Flexibility and small pockets at protein–protein interfaces: New insights into druggability

Jubb

Blundell

Ascher

2015

Progress in Biophysics and Molecular Biology

132

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The transient assembly of multiprotein complexes mediates many aspects of cell regulation and signalling in living organisms. Modulation of the formation of these complexes through targeting protein–protein interfaces can offer greater selectivity than the inhibition of protein kinases, proteases or other post-translational regulatory enzymes using substrate, co-factor or transition state mimetics. However, capitalising on protein–protein interaction interfaces as drug targets has been hindered by the nature of interfaces that tend to offer binding sites lacking the well-defined large cavities of classical drug targets. In this review we posit that interfaces formed by concerted folding and binding (disorder-to-order transitions on binding) of one partner and other examples of interfaces where a protein partner is bound through a continuous epitope from a surface-exposed helix, flexible loop or chain extension may be more tractable for the development of “orthosteric”, competitive chemical modulators; these interfaces tend to offer small-volume but deep pockets and/or larger grooves that may be bound tightly by small chemical entities. We discuss examples of such protein–protein interaction interfaces for which successful chemical modulators are being developed.

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Section: Flexibility In Partner Interactionsmentioning

confidence: 97%

Flexibility and small pockets at protein–protein interfaces: New insights into druggability

Jubb

Blundell

Ascher

2015

Progress in Biophysics and Molecular Biology

132

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“…Many of the latter group involve flexible polypeptides or disordered regions of polypeptide chains that assemble with a more classical globular protein to give a globular complex (Wright & Dyson, 1999, 2009). Schwyzer proposed this idea for polypeptide hormones in the 1970s (Schwyzer et al 1979). It was exemplified by glucagon where biophysical and X-ray analyses (Sasaki et al 1975) together with NMR studies in a lipid–water interface (Braun et al 1983) suggested a disorder-to-order transition of the polypeptide on receptor binding (Blundell, 1979; Blundell & Wood, 1982).…”

Section: Ppis and Their Chemical Modulatorsmentioning

confidence: 99%

Biophysical and computational fragment-based approaches to targeting protein–protein interactions: applications in structure-guided drug discovery

Winter

Higueruelo

Marsh

et al. 2012

Quart. Rev. Biophys.

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Drug discovery has classically targeted the active sites of enzymes or ligand-binding sites of receptors and ion channels. In an attempt to improve selectivity of drug candidates, modulation of protein-protein interfaces (PPIs) of multiprotein complexes that mediate conformation or colocation of components of cell-regulatory pathways has become a focus of interest. However, PPIs in multiprotein systems continue to pose significant challenges, as they are generally large, flat and poor in distinguishing features, making the design of small molecule antagonists a difficult task. Nevertheless, encouragement has come from the recognition that a few amino acids - so-called hotspots - may contribute the majority of interaction-free energy. The challenges posed by protein-protein interactions have led to a wellspring of creative approaches, including proteomimetics, stapled α-helical peptides and a plethora of antibody inspired molecular designs. Here, we review a more generic approach: fragment-based drug discovery. Fragments allow novel areas of chemical space to be explored more efficiently, but the initial hits have low affinity. This means that they will not normally disrupt PPIs, unless they are tethered, an approach that has been pioneered by Wells and co-workers. An alternative fragment-based approach is to stabilise the uncomplexed components of the multiprotein system in solution and employ conventional fragment-based screening. Here, we describe the current knowledge of the structures and properties of protein-protein interactions and the small molecules that can modulate them. We then describe the use of sensitive biophysical methods - nuclear magnetic resonance, X-ray crystallography, surface plasmon resonance, differential scanning fluorimetry or isothermal calorimetry - to screen and validate fragment binding. Fragment hits can subsequently be evolved into larger molecules with higher affinity and potency. These may provide new leads for drug candidates that target protein-protein interactions and have therapeutic value.

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Tobacco mosaic virus as a carrier for small molecules: Artificial receptor antibodies and superhormones

Schwyzer

Kriwaczek

1981

Biopolymers

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SynopsisPeptide agonists covalently attached to tobacco mosaic virus exhibit such unusual properties as superpotency, superaffinity, enhanced resistance towards enzymic degradation, and prolonged action at the target cell. These properties can be exploited for the isolation by density-gradient centrifugation of membrane vesicles bearing specific receptors for the peptides and for radioactive and fluorescent labeling of cell-surface receptors. Our observations can be explained by cooperative-affinity phenomena caused by the deployment in space of the agonist molecules. DEPLOYMENT OF AGONIST MOLECULES AS A FACTOR IN BIOLOGICAL ACTIVITYSince early work on the conformation of cyclic peptides and on the organization of information in linear peptide agonists (for reviews, see Refs. 1-3), it has become increasingly clear that there exist causal relationships between the amino acid sequences of peptides, their conformational possibilities, their interactions with receptors, and their biological activity. In this review, we would like to point out the importance of another factor governing receptor interactions and biological activity, namely the deployment in space of groups of individual agonist molecules. Cooperative AffinityThe strong affinity of antibodies for membrane-bound antigens has been explained by the simultaneous binding of the two recognition sites on the antibody molecule to two antigen molecules connected through the membrane.4.5 Cooperative affinity effects of this type should prevail in any situation in which ligand and acceptor each possess more than one mutual recognition or binding site, provided that these sites are deployed in such a manner that simultaneous interaction is stereochemically feasible. A classical example of almost perfect complementarity is the DNA double helix, in which one single strand can be regarded as the ligand and the other as the acceptor molecule, both containing favorably deployed binding sites: the purine and pyrimidine bases.

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Hormone-receptor interactions: a study of the binding of hormone-substituted tobacco mosaic virus to membrane vesicles by dynamic light scattering and by transient electric bi-refringence

Cited by 8 publications

References 2 publications

Flexibility and small pockets at protein–protein interfaces: New insights into druggability

Flexibility and small pockets at protein–protein interfaces: New insights into druggability

Biophysical and computational fragment-based approaches to targeting protein–protein interactions: applications in structure-guided drug discovery

Tobacco mosaic virus as a carrier for small molecules: Artificial receptor antibodies and superhormones

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