Excited-State Control of Protein Activity

Vendruscolo, Michele

doi:10.1016/j.jmb.2011.07.047

Cited by 2 publications

(3 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the free energy landscape view of protein behavior, native states of proteins may often involve an equilibrium between different substates in rapid conformational exchange. − In these cases, the NMR measurement of an observable D reports on the average value of the observable across N substates D = prefix∑ k p k D k where k runs over the N substates, which have populations p k and values D k of the observable D . In the case of a single substate ( N = 1), eq 3 corresponds to the standard structure determination problem, in which one determines the structure of a protein given a set of experimental data.…”

Section: Resultsmentioning

confidence: 99%

“…These excited states are often important in enzymatic reactions and molecular recognition events, as they include the conformations that are selected by ligands or binding partners 5–8 . NMR spectroscopy can provide detailed information about excited states at atomic level 4–7 .…”

Section: Introductionmentioning

confidence: 99%

“…As proteins in solution undergo conformational fluctuations, in addition to the native structure they can populate other states with smaller populations and higher free energies. − These excited states are often important in enzymatic reactions and molecular recognition events, as they include the conformations that are selected by ligands or binding partners. − Nuclear magnetic resonance (NMR) spectroscopy can provide detailed information about such excited states at the atomic level. − For instance, structural properties of these states can be obtained by the analysis of resonance line widths or by nuclear spin relaxation measurements. ,,, Another powerful approach exploits the introduction of partially aligned samples, which allows one to reintroduce anisotropy in the NMR observables and determine simultaneously the structure and dynamics of proteins. − The measurement of residual dipolar couplings (RDCs) makes it possible not only to characterize the ground states of the macromolecules but also to gain access to the structural features of excited states. , This approach was recently illustrated in the case of membrane proteins by the characterization of the pH-triggered activated-state conformations of the influenza hemagglutinin fusion peptide …”

mentioning

confidence: 99%

See 2 more Smart Citations

Structures of the Excited States of Phospholamban and Shifts in Their Populations upon Phosphorylation

et al. 2013

Self Cite

View full text Add to dashboard Cite

Phospholamban is an integral membrane protein that controls the calcium balance in cardiac muscle cells. As the function and regulation of this protein require the active involvement of low populated states in equilibrium with the native state, it is of great interest to acquire structural information about them. In this work we determine the conformations and populations of the ground state and the three main excited states of phospholamban by incorporating nuclear magnetic resonance (NMR) residual dipolar couplings (RDCs) as replica-averaged structural restraints in molecular dynamics simulations. We then provide a description of the manner in which phosphorylation at Ser16 modulates the activity of the protein by increasing the populations of its excited states. These results demonstrate that approach that we describe provides a detailed characterisation of the different states of phospholamban that determine the function and regulation of this membrane protein. We anticipate that the availability of conformational ensembles will provide opportunities for the development of therapeutic strategies to control the activity of phospholamban by modulating the relative populations of its conformational substates.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Structures of the Excited States of Phospholamban and Shifts in Their Populations upon Phosphorylation

et al. 2013

Self Cite

View full text Add to dashboard Cite

show abstract

Allosteric inhibition through suppression of transient conformational states

Tzeng

Kalodimos

2013

Nat Chem Biol

View full text Add to dashboard Cite

The ability to inhibit binding or enzymatic activity is key to preventing aberrant behaviors of proteins. Allosteric inhibition is desirable as it offers several advantages over competitive inhibition, but the mechanisms of action remain poorly understood in most cases. Here we show that allosteric inhibition can be effected by destabilizing a low-populated conformational state that serves as an on-pathway intermediate for ligand binding, without altering the protein's ground-state structure. As standard structural approaches are typically concerned with changes in the ground-state structure of proteins, the presence of such a mechanism can go easily undetected. Our data strongly argue for the routine use of NMR tools suited to detect and characterize transiently formed conformational states in allosteric systems. Structure information on such important intermediates can ultimately result in more efficient design of allosteric inhibitors.

show abstract

Excited-State Control of Protein Activity

Cited by 2 publications

References 11 publications

Structures of the Excited States of Phospholamban and Shifts in Their Populations upon Phosphorylation

Structures of the Excited States of Phospholamban and Shifts in Their Populations upon Phosphorylation

Allosteric inhibition through suppression of transient conformational states

Contact Info

Product

Resources

About