The Molecules of Life

Kuriyan, John; Konforti, Boyana; Wemmer, David E.

doi:10.1201/9780429258787

Cited by 94 publications

(90 citation statements)

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“…The specificity of an interaction reflects the preference for a protein to bind one particular ligand over another; specificity is a measure of a protein’s relative affinity for different ligands[21]. Because mutations within MarA’s hydrophobic core can abolish binding by destabilizing the native conformation relative to the unfolded conformation, we hypothesized that core mutations could actually alter binding specificity by destabilizing certain native conformations relative to others.…”

Section: Resultsmentioning

confidence: 99%

When the Scaffold Cannot Be Ignored: The Role of the Hydrophobic Core in Ligand Binding and Specificity

Koulechova

Tripp

Horner

et al. 2015

Journal of Molecular Biology

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The traditional view of protein-ligand binding treats a protein as comprising distinct binding epitopes on the surface of a degenerate structural scaffold, largely ignoring the impact of a protein’s energy landscape. To determine the robustness of this simplification, we compared two small helix-turn-helix transcription factors with different energy landscapes. λ-repressor is stable and well folded, while MarA appears to be marginally stable with multiple native conformations (molten). While λ-repressor is known to tolerate any hydrophobic mutation in the core, we find MarA drastically less tolerant to core mutation. Moreover, core mutations in MarA (distant from the DNA-binding interface) change the relative affinities of its binding partners, altering ligand specificity. These results can be explained by taking into account the effects of mutations on the entire energy landscape and not just the native state. Thus, for proteins with multiple conformations that are close in energy, such as many intrinsically disordered proteins, residues distant from the active site can alter both binding affinity and specificity.

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Section: Resultsmentioning

confidence: 99%

When the Scaffold Cannot Be Ignored: The Role of the Hydrophobic Core in Ligand Binding and Specificity

Koulechova

Tripp

Horner

et al. 2015

Journal of Molecular Biology

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“…1 Noncovalent interactions form the basis of molecular recognition, enabling matter to self-organize and emerge into complex structures. For these reasons, it is the recurring leitmotif of molecular biology 2 (nucleic acid base-pairing, receptor–ligand specificity, protein folding, enzyme catalysis, membrane biophysics) and is increasingly exploited in new frontiers of synthesis based on self-assembly (DNA origami, crystal engineering, 3 reticular/framework materials, 4 and hybrid materials).…”

Section: Motivation and Backgroundmentioning

confidence: 99%

Measuring Electric Fields and Noncovalent Interactions Using the Vibrational Stark Effect

Fried¹,

2015

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CONSPECTUS Over the past decade, we have developed a spectroscopic approach to measure electric fields inside matter with high spatial (<1 Å) and field (<1 MV/cm) resolution. The approach hinges on exploiting a physical phenomenon known as the vibrational Stark effect (VSE), which ultimately provides a direct mapping between observed vibrational frequencies and electric fields. Therefore, the frequency of a vibrational probe encodes information about the local electric field in the vicinity around the probe. The VSE method has enabled us to understand in great detail the underlying physical nature of several important biomolecular phenomena, such as drug–receptor selectivity in tyrosine kinases, catalysis by the enzyme ketosteroid isomerase, and unidirectional electron transfer in the photosynthetic reaction center. Beyond these specific examples, the VSE has provided a conceptual foundation for how to model intermolecular (noncovalent) interactions in a quantitative, consistent, and general manner. The starting point for research in this area is to choose (or design) a vibrational probe to interrogate the particular system of interest. Vibrational probes are sometimes intrinsic to the system in question, but we have also devised ways to build them into the system (extrinsic probes), often with minimal perturbation. With modern instruments, vibrational frequencies can increasingly be recorded with very high spatial, temporal, and frequency resolution, affording electric field maps correspondingly resolved in space, time, and field magnitude. In this Account, we set out to explain the VSE in broad strokes to make its relevance accessible to chemists of all specialties. Our intention is not to provide an encyclopedic review of published work but rather to motivate the underlying framework of the methodology and to describe how we make and interpret the measurements. Using certain vibrational probes, benchmarked against computer models, it is possible to use the VSE to measure absolute electric fields in arbitrary environments. The VSE approach provides an organizing framework for thinking generally about intermolecular interactions in a quantitative way and may serve as a useful conceptual tool for molecular design.

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“…Within the ES complex, substrate strain can also elevate the energy of the ground state, further facilitating TS formation. Thus enzymes massively enhance the rate at which equilibrium is attained; for example, catalase achieves a 10 12 -fold enhancement of the rate of H 2 O 2 decomposition (Nelson and Cox, 2000, Chapter 8; Kuriyan et al ., 2013, Chapter 16). Such stabilization of the TS by complementary fit between E and TS is a feature of the catalysis of ATP hydrolysis by the active site of the myosin-2 motor domain, for example.…”

Section: Enzyme-catalyzed Reactionsmentioning

confidence: 99%

Compare and contrast the reaction coordinate diagrams for chemical reactions and cytoskeletal force generators

Scholey

2013

MBoC

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Reaction coordinate diagrams are used to relate the free energy changes that occur during the progress of chemical processes to the rate and equilibrium constants of the process. Here I briefly review the application of these diagrams to the thermodynamics and kinetics of the generation of force and motion by cytoskeletal motors and polymer ratchets as they mediate intracellular transport, organelle dynamics, cell locomotion, and cell division. To provide a familiar biochemical context for discussing these subcellular force generators, I first review the application of reaction coordinate diagrams to the mechanisms of simple chemical and enzyme-catalyzed reactions. My description of reaction coordinate diagrams of motors and polymer ratchets is simplified relative to the rigorous biophysical treatment found in many of the references that I use and cite, but I hope that the essay provides a valuable qualitative representation of the physical chemical parameters that underlie the generation of force and motility at molecular scales. In any case, I have found that this approach represents a useful interdisciplinary framework for understanding, researching, and teaching the basic molecular mechanisms by which motors contribute to fundamental cell biological processes.

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The Molecules of Life

Cited by 94 publications

References 0 publications

When the Scaffold Cannot Be Ignored: The Role of the Hydrophobic Core in Ligand Binding and Specificity

When the Scaffold Cannot Be Ignored: The Role of the Hydrophobic Core in Ligand Binding and Specificity

Measuring Electric Fields and Noncovalent Interactions Using the Vibrational Stark Effect

Compare and contrast the reaction coordinate diagrams for chemical reactions and cytoskeletal force generators

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