Assessing the physiological relevance of alternate architectures of the p7 protein of hepatitis C virus in different environments

Holzmann, Nicole; Chipot, Christophe; Pénin, François; Dagognet, François

doi:10.1016/j.bmc.2016.07.063

Cited by 8 publications

(15 citation statements)

References 42 publications

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“…Membrane insertion of the hexameric structure of p7 reported by Chou and co-workers 207 predicted from (A) MemProtMD 195 and (B) a molecular-dynamics trajectory of 150 ns starting from the protein inserted in a thermalized lipid bilayer. 236 Membrane insertion of the hexameric structures of p7 reported by (C) Foster et al 240 and (D) Chandler et al 232 The phosphate and choline moieties are depicted as yellow and ice blue spheres, respectively. The lipids tails are depicted by gray licorice.…”

Section: Studies Of Mps In Dpc Reveal Strengths and Weaknessesmentioning

confidence: 94%

“… 235 These simulations revealed a partial collapse of the oligomeric architecture and full occlusion of the central pore over a 400 ns time scale. In an attempt to address the origin of the discrepant p7 oligomeric structures, discriminating between the effects of the strain and of the solubilizing agent, a series of molecular simulations was carried out in detergent and membrane environments, using strains J4 and EUH1480 projected onto α-helical hairpin 231 , 240 and the horseshoe-like 207 conformations, in conjunction with NMR spectroscopy 236 ( Figure 14 B,C). The simulations underscored the crucial role played by the environment in shaping the monomeric structure of p7, 247 with the lipid bilayer exhibiting a pronounced tendency to stabilize α-helical hairpin motifs, irrespective of the strain.…”

Section: Studies Of Mps In Dpc Reveal Strengths and Weaknessesmentioning

confidence: 99%

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Perturbations of Native Membrane Protein Structure in Alkyl Phosphocholine Detergents: A Critical Assessment of NMR and Biophysical Studies

et al. 2018

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Membrane proteins perform a host of vital cellular functions. Deciphering the molecular mechanisms whereby they fulfill these functions requires detailed biophysical and structural investigations. Detergents have proven pivotal to extract the protein from its native surroundings. Yet, they provide a milieu that departs significantly from that of the biological membrane, to the extent that the structure, the dynamics, and the interactions of membrane proteins in detergents may considerably vary, as compared to the native environment. Understanding the impact of detergents on membrane proteins is, therefore, crucial to assess the biological relevance of results obtained in detergents. Here, we review the strengths and weaknesses of alkyl phosphocholines (or foscholines), the most widely used detergent in solution-NMR studies of membrane proteins. While this class of detergents is often successful for membrane protein solubilization, a growing list of examples points to destabilizing and denaturing properties, in particular for α-helical membrane proteins. Our comprehensive analysis stresses the importance of stringent controls when working with this class of detergents and when analyzing the structure and dynamics of membrane proteins in alkyl phosphocholine detergents.

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Section: Studies Of Mps In Dpc Reveal Strengths and Weaknessesmentioning

confidence: 94%

Section: Studies Of Mps In Dpc Reveal Strengths and Weaknessesmentioning

confidence: 99%

Perturbations of Native Membrane Protein Structure in Alkyl Phosphocholine Detergents: A Critical Assessment of NMR and Biophysical Studies

et al. 2018

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“…In the context of membrane-protein structure determination, dodecylphosphocholine (DPC) has been the subject of much criticism for being a very harsh detergent, prone to induce protein denaturation ( 1 , 2 , 3 , 4 , 5 ). Yet ∼40% of NMR investigations ( 6 ) have utilized this detergent, leading to protein structures ( 7 , 8 , 9 ) possessing a three-dimensional fold at variance with that observed in a different, milder environment ( 10 , 11 , 12 , 13 , 14 ).…”

Section: Main Textmentioning

confidence: 99%

Mitochondrial ADP/ATP Carrier in Dodecylphosphocholine Binds Cardiolipins with Non-native Affinity

Dagognet

Schanda

King

et al. 2017

Biophysical Journal

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Biophysical investigation of membrane proteins generally requires their extraction from native sources using detergents, a step that can lead, possibly irreversibly, to protein denaturation. The propensity of dodecylphosphocholine (DPC), a detergent widely utilized in NMR studies of membrane proteins, to distort their structure has been the subject of much controversy. It has been recently proposed that the binding specificity of the yeast mitochondrial ADP/ATP carrier (yAAC3) toward cardiolipins is preserved in DPC, thereby suggesting that DPC is a suitable environment in which to study membrane proteins. In this communication, we used all-atom molecular dynamics simulations to investigate the specific binding of cardiolipins to yAAC3. Our data demonstrate that the interaction interface observed in a native-like environment differs markedly from that inferred from an NMR investigation in DPC, implying that in this detergent, the protein structure is distorted. We further investigated yAAC3 solubilized in DPC and in the milder dodecylmaltoside with thermal-shift assays. The loss of thermal transition observed in DPC confirms that the protein is no longer properly folded in this environment.

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“…Furthermore, recent studies have questioned the validity of this structure due to potential artefacts caused by alkyl-phosphocholine detergents used as membrane mimetics (31); the original authors contest this notion (32). However, molecular dynamics simulations favour the stability and channel gating characteristics of hairpin-based structures (33,34).…”

Section: Main Text Introductionmentioning

confidence: 99%

Rationally derived inhibitors of hepatitis C virus (HCV) p7 channel activity reveal prospect for bimodal antiviral therapy

Shaw

Gosain

Kalita³

et al. 2020

eLife

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Since the 1960s, a single class of agent has been licensed targeting virus-encoded ion channels, or ‘viroporins’, contrasting the success of channel blocking drugs in other areas of medicine. Although resistance arose to these prototypic adamantane inhibitors of the influenza A virus (IAV) M2 proton channel, a growing number of clinically and economically important viruses are now recognised to encode essential viroporins providing potential targets for modern drug discovery. We describe the first rationally designed viroporin inhibitor with a comprehensive structure-activity relationship (SAR). This step-change in understanding not only revealed a second biological function for the p7 viroporin from hepatitis C virus (HCV) during virus entry, but also enabled the synthesis of a labelled tool compound that retained biological activity. Hence, p7 inhibitors (p7i) represent a unique class of HCV antiviral targeting both the spread and establishment of infection, as well as a precedent for future viroporin-targeted drug discovery.

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Assessing the physiological relevance of alternate architectures of the p7 protein of hepatitis C virus in different environments

Cited by 8 publications

References 42 publications

Perturbations of Native Membrane Protein Structure in Alkyl Phosphocholine Detergents: A Critical Assessment of NMR and Biophysical Studies

Perturbations of Native Membrane Protein Structure in Alkyl Phosphocholine Detergents: A Critical Assessment of NMR and Biophysical Studies

Mitochondrial ADP/ATP Carrier in Dodecylphosphocholine Binds Cardiolipins with Non-native Affinity

Rationally derived inhibitors of hepatitis C virus (HCV) p7 channel activity reveal prospect for bimodal antiviral therapy

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