ArticleProceedings of the National Academy of Sciences of the United States of America2015
Inactive conformation enhances binding function in physiological conditions.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 28 citations in OpenAlex.
- Review
- Antibodies disrupt bacterial adhesion by ligand mimicry and allosteric interference.Nature communications · 2025Article
- FimH-mannose noncovalent bonds survive minutes to hours under force.Biophysical journal · 2024Article
- Effect of Gravity on Bacterial Adhesion to Heterogeneous Surfaces.Pathogens (Basel, Switzerland) · 2023Article
- Neutralizing Antibodies Against Allosteric Proteins: Insights From a Bacterial Adhesin.Journal of molecular biology · 2022Review
- Recombinant FimH Adhesin Demonstrates How the Allosteric Catch Bond Mechanism Can Support Fast and Strong Bacterial Attachment in the Absence of Shear.Journal of molecular biology · 2022Article
- Correlating single-molecule rupture mechanics with cell population adhesion by yeast display.Biophysical reports · 2022Article
- Single-molecule imaging of von Willebrand factor reveals tension-dependent self-association.Blood · 2021Article
- Low-affinity integrin states have faster ligand-binding kinetics than the high-affinity state.eLife · 2021Article
- Toggle switch residues control allosteric transitions in bacterial adhesins by participating in a concerted repacking of the protein core.PLoS pathogens · 2021Article
- Conformational stability of the bacterial adhesin, FimH, with an inactivating mutation.Proteins · 2021Article
- FimH as a scaffold for regulated molecular recognition.Journal of biological engineering · 2021Article
- Pili Assembled by the Chaperone/Usher Pathway inEcoSal Plus · 2018Review
- High integrin αProceedings of the National Academy of Sciences of the United States of America · 2018Article
- Conformational switch of the bacterial adhesin FimH in the absence of the regulatory domain: Engineering a minimalistic allosteric system.The Journal of biological chemistry · 2018Article
- Rational design strategies for FimH antagonists: new drugs on the horizon for urinary tract infection and Crohn's disease.Expert opinion on drug discovery · 2017Review
- Adhesion of Escherichia coli under flow conditions reveals potential novel effects of FimH mutations.European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology · 2017Article
- Glycan Bound to the Selectin Low Affinity State Engages Glu-88 to Stabilize the High Affinity State under Force.The Journal of biological chemistry · 2017Article
- Evolutionary fine-tuning of conformational ensembles in FimH during host-pathogen interactions.Science advances · 2017Article
- Mechanism of allosteric propagation across a β-sheet structure investigated by molecular dynamics simulations.Proteins · 2016Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Many receptors display conformational flexibility, in which the binding pocket has an open inactive conformation in the absence of ligand and a tight active conformation when bound to ligand. Here we study the bacterial adhesin FimH to address the role of the inactive conformation of the pocket for initiating binding by comparing two variants: a wild-type FimH variant that is in the inactive state when not bound to its target mannose, and an engineered activated variant that is always in the active state. Not surprisingly, activated FimH has a longer lifetime and higher affinity, and bacteria expressing activated FimH bound better in static conditions. However, bacteria expressing wild-type FimH bound better in flow. Wild-type and activated FimH demonstrated similar mechanical strength, likely because mechanical force induces the active state in wild-type FimH. However, wild-type FimH displayed a faster bond association rate than activated FimH. Moreover, the ability of different FimH variants to mediate adhesion in flow reflected the fraction of FimH in the inactive state. These results demonstrate a new model for ligand-associated conformational changes that we call the kinetic-selection model, in which ligand-binding selects the faster-binding inactive state and then induces the active state. This model predicts that in physiological conditions for cell adhesion, mechanical force will drive a nonequilibrium cycle that uses the fast binding rate of the inactive state and slow unbinding rate of the active state, for a higher effective affinity than is possible at equilibrium.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.