Mechanism of allosteric propagation across a β‐sheet structure investigated by molecular dynamics simulations

Interlandi, Gianluca; Thomas, Wendy E.

doi:10.1002/prot.25050

Cited by 18 publications

(42 citation statements)

References 64 publications

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“…Our data for the three mutants V67K, R60P, and V27C/L34C are in good agreement with MD simulations of FimH LD , indicating a weak coupling of the binding pocket to the ␣-switch region (V67K) but a strong coupling to the ␤-bulge (R60P) and to the interdomain regions (V27C/L34C) (26). These couplings are supposed to regulate the dynamics in the clamp loop near the binding pocket and to cause the renowned catch-bond behavior of FimH.…”

Section: Allosteric Regulation Of the Bacterial Adhesin Fimhsupporting

confidence: 82%

“…In summary, the loss in affinity for R60P and especially for V27C/ L34C mainly originates from enhanced k off values, which is in agreement with the concept of a dynamic allostery, i.e. the binding pockets in the medium-and high-affinity states of FimH have nearly identical geometries, although the off-rates are modulated by the flexibility of the binding pocket and the clamp loop (23,26). Consequently, we focused in the following sections on the two most interesting variants (R60P and V27C/ L34C) and the mutant A119L for comparison with an unaffected variant.…”

Section: Similar Binding Kinetics For V27c/l34c Mutant and Wt Fimh Flsupporting

confidence: 82%

“…Interestingly, the medium-affinity state (domains interacting) and the high-affinity state (domains separated) exhibit nearly identical mannose-binding pockets, yet possess a strikingly 10 5 -fold difference in the off-rate for mannosides (23). This structural information in combination with MD simulations and kinetics experiments (23,26) led to the concept of dynamic allosteric regulation, i.e. the allosteric signal of the pilin domain is transmitted to the proximal regions of the lectin domain, whereas the binding pocket is regulated purely by protein dynamics (27).…”

mentioning

confidence: 83%

“…These couplings are supposed to regulate the dynamics in the clamp loop near the binding pocket and to cause the renowned catch-bond behavior of FimH. A higher flexibility of the clamp loop in the medium-affinity state could be responsible for the dramatically enhanced off-rates for mannosides relative to the high-affinity state, despite nearly identical conformation of the binding pocket (23,26).…”

Section: Allosteric Regulation Of the Bacterial Adhesin Fimhmentioning

confidence: 99%

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Conformational switch of the bacterial adhesin FimH in the absence of the regulatory domain: Engineering a minimalistic allosteric system

Rabbani

Fiege

Eriş

et al. 2018

Journal of Biological Chemistry

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Edited by Wolfgang Peti For many biological processes such as ligand binding, enzymatic catalysis, or protein folding, allosteric regulation of protein conformation and dynamics is fundamentally important. One example is the bacterial adhesin FimH, where the C-terminal pilin domain exerts negative allosteric control over binding of the N-terminal lectin domain to mannosylated ligands on host cells. When the lectin and pilin domains are separated under shear stress, the FimH-ligand interaction switches in a so-called catch-bond mechanism from the low-to high-affinity state. So far, it has been assumed that the pilin domain is essential for the allosteric propagation within the lectin domain that would otherwise be conformationally rigid. To test this hypothesis, we generated mutants of the isolated FimH lectin domain and characterized their thermodynamic, kinetic, and structural properties using isothermal titration calorimetry, surface plasmon resonance, nuclear magnetic resonance, and X-ray techniques. Intriguingly, some of the mutants mimicked the conformational and kinetic behaviors of the full-length protein and, even in absence of the pilin domain, conducted the cross-talk between allosteric sites and the mannoside-binding pocket. Thus, these mutants represent a minimalistic allosteric system of FimH, useful for further mechanistic studies and antagonist design. The authors declare that they have no conflicts of interest with the contents of this article. This article contains Figs. S1-S11, Tables S1-S2, supporting Extended Experimental procedures, and supporting Refs. 1-5. The atomic coordinates and structure factors (code 5MCA) have been deposited in the Protein Data Bank (http://wwpdb.org/).

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Section: Allosteric Regulation Of the Bacterial Adhesin Fimhsupporting

confidence: 82%

Section: Similar Binding Kinetics For V27c/l34c Mutant and Wt Fimh Flsupporting

confidence: 82%

mentioning

confidence: 83%

Section: Allosteric Regulation Of the Bacterial Adhesin Fimhmentioning

confidence: 99%

See 2 more Smart Citations

Conformational switch of the bacterial adhesin FimH in the absence of the regulatory domain: Engineering a minimalistic allosteric system

Rabbani

Fiege

Eriş

et al. 2018

Journal of Biological Chemistry

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“…10 to 15), which closes the binding site in response to mannose binding (see Figure 3 ), have also been identified as significantly changing their conformation in an extended MD study of the FimH HA/LA change using the Anton supercomputer [ 65 ]. Based on crystallographic data [ 57 ] and MD simulations [ 65 ], a large β-strand (aa. 16 to 22) connecting the clamp loop was identified as mediator to propagate the allosteric signal from the binding site to the pilin domain.…”

Section: The Molecular Binding Mechanism Of Small Mannosidic Compomentioning

confidence: 99%

Targeting Dynamical Binding Processes in the Design of Non-Antibiotic Anti-Adhesives by Molecular Simulation—The Example of FimH

et al. 2018

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Located at the tip of type I fimbria of Escherichia coli, the bacterial adhesin FimH is responsible for the attachment of the bacteria to the (human) host by specifically binding to highly-mannosylated glycoproteins located on the exterior of the host cell wall. Adhesion represents a necessary early step in bacterial infection and specific inhibition of this process represents a valuable alternative pathway to antibiotic treatments, as such anti-adhesive drugs are non-intrusive and are therefore unlikely to induce bacterial resistance. The currently available anti-adhesives with the highest affinities for FimH still feature affinities in the nanomolar range. A prerequisite to develop higher-affinity FimH inhibitors is a molecular understanding of the FimH-inhibitor complex formation. The latest insights in the formation process are achieved by combining several molecular simulation and traditional experimental techniques. This review summarizes how molecular simulation contributed to the current knowledge of the molecular function of FimH and the importance of dynamics in the inhibitor binding process, and highlights the importance of the incorporation of dynamical aspects in (future) drug-design studies.

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Chemical and Biophysical Approaches to Allosteric Modulation

Civera

Moroni²,

Sorrentino

et al. 2021

Eur J Org Chem

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Allosteric regulation, i. e. the control exerted on an orthosteric site by an effector interacting at a distinct and distant site, represents a prime example of a precise tuning system of several key biological processes like gene transcription, cell adhesion and, most importantly, signal transduction. Since its discovery sixty years ago, the molecular mechanisms underlying this phenomenon have been extensively investigated. The aim of this minireview is to introduce the reader to the topic of protein allostery. In particular, we briefly overview the allosteric models postulated over the years and we describe the most relevant chemical and biophysical approaches reported so far for the identification of putative allosteric sites and/or for the investigation of allosteric signal propagation throughout the protein. An outlook of the main computational and experimental methods is followed by four case studies representative of different proteins classes: enzymes, hub proteins, cell receptors, and intrinsically disordered proteins.

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Mechanism of allosteric propagation across a β‐sheet structure investigated by molecular dynamics simulations

Cited by 18 publications

References 64 publications

Conformational switch of the bacterial adhesin FimH in the absence of the regulatory domain: Engineering a minimalistic allosteric system

Conformational switch of the bacterial adhesin FimH in the absence of the regulatory domain: Engineering a minimalistic allosteric system

Targeting Dynamical Binding Processes in the Design of Non-Antibiotic Anti-Adhesives by Molecular Simulation—The Example of FimH

Chemical and Biophysical Approaches to Allosteric Modulation

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