On the nature of allosteric transitions: A plausible model

Monod, Jacques; Wyman, Jeffries; Changeux, Jean‐Pierre

doi:10.1016/s0022-2836(65)80285-6

Cited by 8,412 publications

(4,383 citation statements)

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“…Similarly, mannose is likely to stabilize the closed conformation of the clamp segment. Classic models of allostery focused on whether allosteric conformational changes happen sequentially40 or whether they must happen simultaneously in a concerted fashion 2. The mechanism of the lectin domain is a combination of both.…”

Section: Discussionmentioning

confidence: 99%

“…Protein allostery is generally described as the regulation of the active site of a protein through an effector binding to a distal location and triggering or stabilizing a conformational transition across the protein 1, 2. As a result, allosterically regulated proteins can be found natively in two distinct states depending whether the effector is bound or not.…”

Section: Introductionmentioning

confidence: 99%

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

Interlandi

Thomas

2016

Proteins

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The bacterial adhesin FimH consists of an allosterically regulated mannose‐binding lectin domain and a covalently linked inhibitory pilin domain. Under normal conditions, the two domains are bound to each other, and FimH interacts weakly with mannose. However, under tensile force, the domains separate and the lectin domain undergoes conformational changes that strengthen its bond with mannose. Comparison of the crystallographic structures of the low and the high affinity state of the lectin domain reveals conformational changes mainly in the regulatory inter‐domain region, the mannose binding site and a large β sheet that connects the two distally located regions. Here, molecular dynamics simulations investigated how conformational changes are propagated within and between different regions of the lectin domain. It was found that the inter‐domain region moves towards the high affinity conformation as it becomes more compact and buries exposed hydrophobic surface after separation of the pilin domain. The mannose binding site was more rigid in the high affinity state, which prevented water penetration into the pocket. The large central β sheet demonstrated a soft spring‐like twisting. Its twisting motion was moderately correlated to fluctuations in both the regulatory and the binding region, whereas a weak correlation was seen in a direct comparison of these two distal sites. The results suggest a so called “population shift” model whereby binding of the lectin domain to either the pilin domain or mannose locks the β sheet in a rather twisted or flat conformation, stabilizing the low or the high affinity state, respectively. Proteins 2016; 84:990–1008. © 2016 The Authors. Proteins: Structure, Function, and Bioinformatics Published by Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Interlandi

Thomas

2016

Proteins

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“…The first component, MCP complex, was represented with a Monod–Wyman–Changeux (MWC) model52 to describe the allosteric effects of receptor clusters with identical receptors. Each MCP complex switched rapidly between active (on) and inactive (off) states, determined by a free‐energy difference F as follows37, 41, 42

F (m, [L]) = f_{m} (m) + \ln (1 + \frac{false[L false]}{K_{a}}) - \ln (1 normal + normal \frac{false[L false]}{K_{i}})

where m is the total methylation level of the receptor complex, [ L ] indicates the ligand concentration, K a and K i are the dissociation constants of active and inactive receptors, respectively, and f m ( m ) = α( m 0 − m ), with α ≈ 1.7 and m 0 ≈ 1,53 is the methylation level‐dependent free energy difference.…”

Section: Methodsmentioning

confidence: 99%

Propulsion and Chemotaxis in Bacteria‐Driven Microswimmers

2017

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Despite the large body of experimental work recently on biohybrid microsystems, few studies have focused on theoretical modeling of such systems, which is essential to understand their underlying functioning mechanisms and hence design them optimally for a given application task. Therefore, this study focuses on developing a mathematical model to describe the 3D motion and chemotaxis of a type of widely studied biohybrid microswimmer, where spherical microbeads are driven by multiple attached bacteria. The model is developed based on the biophysical observations of the experimental system and is validated by comparing the model simulation with experimental 3D swimming trajectories and other motility characteristics, including mean squared displacement, speed, diffusivity, and turn angle. The chemotaxis modeling results of the microswimmers also agree well with the experiments, where a collective chemotactic behavior among multiple bacteria is observed. The simulation result implies that such collective chemotaxis behavior is due to a synchronized signaling pathway across the bacteria attached to the same microswimmer. Furthermore, the dependencies of the motility and chemotaxis of the microswimmers on certain system parameters, such as the chemoattractant concentration gradient, swimmer body size, and number of attached bacteria, toward an optimized design of such biohybrid system are studied. The optimized microswimmers would be used in targeted cargo, e.g., drug, imaging agent, gene, and RNA, transport and delivery inside the stagnant or low‐velocity fluids of the human body as one of their potential biomedical applications.

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“…At phosphoenolpyruvate concentrations as low as 0.02 mM this requirement cannot be easily fulfilled. For L4 pyruvate kinase from human liver the model would reduce to a simple R # T model [8]. The 1~ form would be stabilized by phosphoenolpyruvate and fructose 1,6-diphosphate, the T form by ATP.…”

Section: Discussionmentioning

confidence: 99%

Functional changes associated with the sequential transformation of L′4 into L4 pyruvate kinase

Sprengers

Staal

1979

Biochimica et Biophysica Acta (BBA) - Enzymology

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SummaryThe functional changes, associated with the sequential transformation of L:~ into L4 pyruvate kinase (ATP:pyruvate 2-O-phosphotransferase, EC 2.7.1.40) were studied. L~ enzyme from human erythrocytes shows strong hysteretic behaviour: the initial rate of the enzyme preincubated with an unsaturating concentration of phosphoenolpyruvate is much higher than of the enzyme preincubated with ADP, at the same phosphoenolpyruvate concentration, although the 'final activity' (the activity of the linear part of the reaction progress curve) was the same in both cases. This phenomenon was observed both in the presence and absence of fructose 1,6-diphosphate. High concentrations of both 2÷ Mg~ree and MgATP 2-diminish the difference in initial rate, between the ADP and phosphoenolpyruvate preincubated enzymes: 2+ Mgfre e by stabilizing the phosphoenolpyruvate-induced form; ATPMg 2-by stabilizing the ADP-induced form. The magnitude of the difference in initial rates of the ADPor phosphoenolpyruvate-preincubated enzyme is a function of both substrates. L, pyruvate kinase(either from human liver or trypsin treated L~ enzyme) does not, or to a very slight extent, show such behaviour. L~L2 pyruvate kinase shows behaviour intermediate between L~ and L4 enzymes.A model is proposed to describe the kinetic behaviour of L~ and L4 enzymes.

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On the nature of allosteric transitions: A plausible model

Cited by 8,412 publications

References 48 publications

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

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

Propulsion and Chemotaxis in Bacteria‐Driven Microswimmers

Functional changes associated with the sequential transformation of L′4 into L4 pyruvate kinase

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