An NMR View of Protein Dynamics in Health and Disease

Sekhar, Ashok; Kay, Lewis E.

doi:10.1146/annurev-biophys-052118-115647

Cited by 129 publications

(102 citation statements)

References 146 publications

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“…Solution-state NMR spectroscopy is the primary experimental technique for the dynamical characterization of proteins at atomic resolution [ 121 , 122 , 123 , 124 , 125 ], which can serve as a proxy for conformational entropy. In the simplest terms, the conformational entropy of a protein can be described by the total number of conformations that are accessible to the protein under a defined set of macroscopic conditions (e.g., protein concentration, temperature, and volume).…”

Section: Idrs Feature High Conformational Entropymentioning

confidence: 99%

Entropy and Information within Intrinsically Disordered Protein Regions

Pritišanac

Vernon

Moses

et al. 2019

Entropy

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Bioinformatics and biophysical studies of intrinsically disordered proteins and regions (IDRs) note the high entropy at individual sequence positions and in conformations sampled in solution. This prevents application of the canonical sequence-structure-function paradigm to IDRs and motivates the development of new methods to extract information from IDR sequences. We argue that the information in IDR sequences cannot be fully revealed through positional conservation, which largely measures stable structural contacts and interaction motifs. Instead, considerations of evolutionary conservation of molecular features can reveal the full extent of information in IDRs. Experimental quantification of the large conformational entropy of IDRs is challenging but can be approximated through the extent of conformational sampling measured by a combination of NMR spectroscopy and lower-resolution structural biology techniques, which can be further interpreted with simulations. Conformational entropy and other biophysical features can be modulated by post-translational modifications that provide functional advantages to IDRs by tuning their energy landscapes and enabling a variety of functional interactions and modes of regulation. The diverse mosaic of functional states of IDRs and their conformational features within complexes demands novel metrics of information, which will reflect the complicated sequence-conformational ensemble-function relationship of IDRs.

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Section: Idrs Feature High Conformational Entropymentioning

confidence: 99%

Entropy and Information within Intrinsically Disordered Protein Regions

Pritišanac

Vernon

Moses

et al. 2019

Entropy

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“…In both panels, motions are schematically depicted by the motion lines. NMR in particular has been a powerful method for identifying changes in mobility of different regions and across different states (Boehr et al, 2006;Frederick et al, 2007;Henzler-Wildman and Kern, 2007;Kumar et al, 2018;Marlow et al, 2010;Sekhar and Kay, 2019;Takeuchi et al, 2015). Nevertheless, NMR dynamic data do not typically provide information on the direction and absolute extent of motion (Kleckner and Foster, 2011;Kovermann et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Assessment of enzyme active site positioning and tests of catalytic mechanisms through X-ray-derived conformational ensembles

Yabukarski¹,

Biel²,

Pinney³

et al. 2019

Preprint

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Our physical understanding of enzyme catalysis has been limited by the scarcity of data for the positioning and motions of groups in and around the active site. To provide foundational information and test fundamental catalytic models, we created conformational ensembles from 45 PDB crystal structures and collected new 'room temperature' X-ray crystallography data for ketosteroid isomerase (KSI). Ensemble analyses indicated substantial pre-positioning and minimal conformational heterogeneity loss through the reaction cycle. The oxyanion hole and general base residues appear conformationally restricted, but not exceptionally so relative to analogous non-catalytic groups. Analysis of surrounding groups and mutant ensembles provide insight into the balance of forces responsible for local conformational preferences. Oxyanion hole catalysis appears to arise from hydrogen bond donors that are stronger than water, without additional catalysis from geometrical discrimination, more distal effects, or environmental alterations. The presence of a range of conformational sub-states presumably facilitates KSI's multiple reaction steps.Classical catalytic proposals invoked static structures of shape and charge complementarity to the reaction's transition state (Eyring). More recently emerging models have emphasized the occurrence of and importance of structural dynamics in protein function and enzyme catalysis (Boehr et al.,

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“…A very recent example of the combined use of NMR and crystallography is reported by Jeganathan et al (2019). The study of flexibility by NMR is seen as offering new drug-discovery routes in pharmaceutical, health and disease research (Peng, 2009;Sekhar & Kay, 2019).…”

Section: Some Historymentioning

confidence: 99%

What is the structural chemistry of the living organism at its temperature and pressure?

Helliwell

2020

Acta Cryst Sect D Struct Biol

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The three probes of the structure of matter (X-rays, neutrons and electrons) in biology have complementary properties and strengths. The balance between these three probes within their strengths and weaknesses is perceived to change, even dramatically so at times. For the study of combined states of order and disorder, NMR crystallography is also applicable. Of course, to understand biological systems the required perspectives are surely physiologically relevant temperatures and relevant chemical conditions, as well as a minimal perturbation owing to the needs of the probe itself. These remain very tough challenges because, for example, cryoEM by its very nature will never be performed at room temperature, crystallization often requires nonphysiological chemical conditions, and X-rays and electrons cause beam damage. However, integrated structural biology techniques and functional assays provide a package towards physiological relevance of any given study. Reporting of protein crystal structures, and their associated database entries, could usefully indicate how close to the biological situation they are, as discussed in detail in this feature article.

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An NMR View of Protein Dynamics in Health and Disease

Cited by 129 publications

References 146 publications

Entropy and Information within Intrinsically Disordered Protein Regions

Entropy and Information within Intrinsically Disordered Protein Regions

Assessment of enzyme active site positioning and tests of catalytic mechanisms through X-ray-derived conformational ensembles

What is the structural chemistry of the living organism at its temperature and pressure?

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