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Žı́dek, Lukáš; Novotný, Miloš V.; Stone, Martin J.

doi:10.1038/70057

Cited by 227 publications

(33 citation statements)

References 39 publications

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“…As for the the major urinary protein, this redistribution of the conformational entropy from one timescale to another may contribute to the stabilisation of the complex by the so-called entropy-entropy compensation effect5758. The persistence of fast-motions in the complex may also be important for the re-opening of the cavity and the release of the ligand.…”

Section: Resultsmentioning

confidence: 99%

STARD6 on steroids: solution structure, multiple timescale backbone dynamics and ligand binding mechanism

Létourneau

Bédard

Cabana

et al. 2016

Sci Rep

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START domain proteins are conserved α/β helix-grip fold that play a role in the non-vesicular and intracellular transport of lipids and sterols. The mechanism and conformational changes permitting the entry of the ligand into their buried binding sites is not well understood. Moreover, their functions and the identification of cognate ligands is still an active area of research. Here, we report the solution structure of STARD6 and the characterization of its backbone dynamics on multiple time-scales through 15N spin-relaxation and amide exchange studies. We reveal for the first time the presence of concerted fluctuations in the Ω1 loop and the C-terminal helix on the microsecond-millisecond time-scale that allows for the opening of the binding site and ligand entry. We also report that STARD6 binds specifically testosterone. Our work represents a milestone for the study of ligand binding mechanism by other START domains and the elucidation of the biological function of STARD6.

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Section: Resultsmentioning

confidence: 99%

STARD6 on steroids: solution structure, multiple timescale backbone dynamics and ligand binding mechanism

Létourneau

Bédard

Cabana

et al. 2016

Sci Rep

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“…Binding-induced increases in side chain flexibility were reported in the pioneering NMR studies inter-relating side chain with conformational entropy (Lee et al 2000), and have since appeared for both side chains and the backbone (e.g. (Bruschweiler et al 2013; Igumenova et al 2006; Iwahara et al 2005; Jarymowycz and Stone 2006; Zidek et al 1999)). Flexibility increases may mitigate unfavorable conformational entropy costs associated with complex formation (Bruschweiler et al 2013).…”

Section: Substrate-induced Changes In Side-chain Dynamics Suggest Dynmentioning

confidence: 97%

Investigating dynamic interdomain allostery in Pin1

Peng

2015

Biophys Rev

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Signaling proteins often sequester complementary functional sites in separate domains. How do the different domains communicate with one another? An attractive system to address this question is the mitotic regulator, human Pin1 (Lu et al. 1996). Pin-1 consists of two tethered domains: a WW domain for substrate binding, and a catalytic domain for peptidyl-prolyl isomerase (PPIase) activity. Pin1 accelerates the cis-trans isomerization of phospho-Ser/Thr-Pro (pS/T-P) motifs within proteins regulating the cell cycle and neuronal development. The early x-ray (Ranganathan et al. 1997; Verdecia et al. 2000) and solution NMR studies (Bayer et al. 2003; Jacobs et al. 2003) of Pin1 indicated inter- and intradomain motion. We became interested in exploring how such motions might affect interdomain communication, using NMR. Our accumulated results indicate substrate binding to Pin1 WW domain changes the intra/inter domain mobility, thereby altering substrate activity in the distal PPIase domain catalytic site. Thus, Pin1 shows evidence of dynamic allostery, in the sense of Cooper and Dryden (Cooper and Dryden 1984). We highlight our results supporting this conclusion, and summarize them via a simple speculative model of conformational selection.

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“…For example, both NMR and computational studies point to large changes in configurational entropy when proteins bind other molecules. 1,3−10 …”

Section: Introductionmentioning

confidence: 99%

“…These changes are often interpreted, at least semiquantitatively, in terms of changes in configurational entropy. 3,5,9−16 However, such NMR data are not directly informative about changes in correlation. As a consequence, it is of interest to consider the nature of correlation contributions to the entropy changes of interest.…”

Section: Introductionmentioning

confidence: 99%

Correlation as a Determinant of Configurational Entropy in Supramolecular and Protein Systems

et al. 2014

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For biomolecules in solution, changes in configurational entropy are thought to contribute substantially to the free energies of processes like binding and conformational change. In principle, the configurational entropy can be strongly affected by pairwise and higher-order correlations among conformational degrees of freedom. However, the literature offers mixed perspectives regarding the contributions that changes in correlations make to changes in configurational entropy for such processes. Here we take advantage of powerful techniques for simulation and entropy analysis to carry out rigorous in silico studies of correlation in binding and conformational changes. In particular, we apply information-theoretic expansions of the configurational entropy to well-sampled molecular dynamics simulations of a model host–guest system and the protein bovine pancreatic trypsin inhibitor. The results bear on the interpretation of NMR data, as they indicate that changes in correlation are important determinants of entropy changes for biologically relevant processes and that changes in correlation may either balance or reinforce changes in first-order entropy. The results also highlight the importance of main-chain torsions as contributors to changes in protein configurational entropy. As simulation techniques grow in power, the mathematical techniques used here will offer new opportunities to answer challenging questions about complex molecular systems.

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Untitled

Cited by 227 publications

References 39 publications

STARD6 on steroids: solution structure, multiple timescale backbone dynamics and ligand binding mechanism

STARD6 on steroids: solution structure, multiple timescale backbone dynamics and ligand binding mechanism

Investigating dynamic interdomain allostery in Pin1

Correlation as a Determinant of Configurational Entropy in Supramolecular and Protein Systems

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