Solution structure and oligomeric state of the E. coliglycerol facilitator

Hernando, Mary; Orriss, George L.; Perodeau, Jacqueline; Lei, Shixing; Ferens, Fraser G.; Patel, Trushar R.; Stetefeld, Jörg; Nieuwkoop, Andrew J.; O'Neil, Joe D. J.

doi:10.1016/j.bbamem.2020.183191

Cited by 6 publications

(4 citation statements)

References 90 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Co-polymers such as styrene-maleic acid have been used to extract membrane proteins and lipids directly from host membranes to form soluble nanoparticles or native nanodiscs, thereby permitting purification of membrane proteins without their removal from a lipid environment [ 105 , 106 ]. Nanodisc technologies have been increasingly used in recent years for studies of bacterial membrane proteins, including SHKs [ 107 , 108 , 109 ], multi-drug efflux transporters [ 110 , 111 ], glycerol facilitators [ 112 ], beta-barrel outer membrane proteins [ 113 , 114 ], ABC transporters [ 115 ] and other bacterial membrane proteins (e.g., [ 116 , 117 ]). Cuozzo and Soutter (2014) reviewed how these newer technologies alongside more traditional detergent-based methods of producing membrane proteins impact on small-molecule screening for antibiotic discovery [ 118 ].…”

Section: Methodology For Producing Purified Active Forms Of Full-length Membrane Shksmentioning

confidence: 99%

Membrane Sensor Histidine Kinases: Insights from Structural, Ligand and Inhibitor Studies of Full-Length Proteins and Signalling Domains for Antibiotic Discovery

Phillips‐Jones

2021

Molecules

View full text Add to dashboard Cite

There is an urgent need to find new antibacterial agents to combat bacterial infections, including agents that inhibit novel, hitherto unexploited targets in bacterial cells. Amongst novel targets are two-component signal transduction systems (TCSs) which are the main mechanism by which bacteria sense and respond to environmental changes. TCSs typically comprise a membrane-embedded sensory protein (the sensor histidine kinase, SHK) and a partner response regulator protein. Amongst promising targets within SHKs are those involved in environmental signal detection (useful for targeting specific SHKs) and the common themes of signal transmission across the membrane and propagation to catalytic domains (for targeting multiple SHKs). However, the nature of environmental signals for the vast majority of SHKs is still lacking, and there is a paucity of structural information based on full-length membrane-bound SHKs with and without ligand. Reasons for this lack of knowledge lie in the technical challenges associated with investigations of these relatively hydrophobic membrane proteins and the inherent flexibility of these multidomain proteins that reduces the chances of successful crystallisation for structural determination by X-ray crystallography. However, in recent years there has been an explosion of information published on (a) methodology for producing active forms of full-length detergent-, liposome- and nanodisc-solubilised membrane SHKs and their use in structural studies and identification of signalling ligands and inhibitors; and (b) mechanisms of signal sensing and transduction across the membrane obtained using sensory and transmembrane domains in isolation, which reveal some commonalities as well as unique features. Here we review the most recent advances in these areas and highlight those of potential use in future strategies for antibiotic discovery. This Review is part of a Special Issue entitled “Interactions of Bacterial Molecules with Their Ligands and Other Chemical Agents” edited by Mary K. Phillips-Jones.

show abstract

Section: Methodology For Producing Purified Active Forms Of Full-length Membrane Shksmentioning

confidence: 99%

Membrane Sensor Histidine Kinases: Insights from Structural, Ligand and Inhibitor Studies of Full-Length Proteins and Signalling Domains for Antibiotic Discovery

Phillips‐Jones

2021

Molecules

View full text Add to dashboard Cite

show abstract

“…X-ray crystallography and more recently cryo-EM have provided a wealth of structural information. However, these studies cannot report on dynamics and are typically performed in non-native environments containing detergents − and crystallization reagents. − SSNMR is uniquely suited to study GPCRs in a native-like lipid environment, providing information on activation, − ligand–receptor interaction, − and conformational dynamics. , Though NMR can provide a wealth of insight into the structure–dynamics relationship of biomolecular processes, − full atomic characterization is predicted upon chemical shift assignment, which is time-intensive. In the absence of assignments, scoring functions can be implemented as a first approximation to begin elucidating system characteristics.…”

Section: Introductionmentioning

confidence: 99%

“… 26 − 28 SSNMR is uniquely suited to study GPCRs in a native-like lipid environment, providing information on activation, 29 − 32 ligand–receptor interaction, 33 − 35 and conformational dynamics. 36 , 37 Though NMR can provide a wealth of insight into the structure–dynamics relationship of biomolecular processes, 38 − 43 full atomic characterization is predicted upon chemical shift assignment, which is time-intensive. In the absence of assignments, scoring functions can be implemented as a first approximation to begin elucidating system characteristics.…”

Section: Introductionmentioning

confidence: 99%

Cholesterol Biases the Conformational Landscape of the Chemokine Receptor CCR3: A MAS SSNMR-Filtered Molecular Dynamics Study

Aalst

McDonald

Wylie

2023

J. Chem. Inf. Model.

View full text Add to dashboard Cite

Cholesterol directs the pathway of ligand-induced G protein-coupled receptor (GPCR) signal transduction. The GPCR C–C motif chemokine receptor 3 (CCR3) is the principal chemotactic receptor for eosinophils, with roles in cancer metastasis and autoinflammatory conditions. Recently, we discovered a direct correlation between bilayer cholesterol and increased agonist-triggered CCR3 signal transduction. However, the allosteric molecular mechanism escalating ligand affinity and G protein coupling is unknown. To study cholesterol-guided CCR3 conformational selection, we implement comparative, objective measurement of protein architectures by scoring shifts (COMPASS) to grade model structures from molecular dynamics simulations. In this workflow, we scored predicted chemical shifts against 2-dimensional solid-state NMR 13C–13C correlation spectra of U–15N,13C-CCR3 samples prepared with and without cholesterol. Our analysis of trajectory model structures uncovers that cholesterol induces site-specific conformational restraint of extracellular loop (ECL) 2 and conserved motion in transmembrane helices and ECL3 not observed in simulations of bilayers with only phosphatidylcholine lipids. PyLipID analysis implicates direct cholesterol agency in CCR3 conformational selection and dynamics. Residue–residue contact scoring shows that cholesterol biases the conformational selection of the orthosteric pocket involving Y411.39, Y1133.32, and E2877.39. Lastly, we observe contact remodeling in activation pathway residues centered on the initial transmission switch, Na+ pocket, and R3.50 in the DRY motif. Our observations have unique implications for understanding of CCR3 ligand recognition and specificity and provide mechanistic insight into how cholesterol functions as an allosteric regulator of CCR3 signal transduction.

show abstract

“…Aquaglyceroporins, a subfamily of membrane proteins belonging to the aquaporin (AQP) family (see, e.g. , ref. 8–75 for the background literature and some recent research), facilitate glycerol diffusion across the cell membrane down the concentration gradient.…”

Section: Introductionmentioning

confidence: 99%

Quantitative study of unsaturated transport of glycerol through aquaglyceroporin that has high affinity for glycerol

et al. 2020

View full text Add to dashboard Cite

show abstract

Solution structure and oligomeric state of the E. coliglycerol facilitator

Cited by 6 publications

References 90 publications

Membrane Sensor Histidine Kinases: Insights from Structural, Ligand and Inhibitor Studies of Full-Length Proteins and Signalling Domains for Antibiotic Discovery

Membrane Sensor Histidine Kinases: Insights from Structural, Ligand and Inhibitor Studies of Full-Length Proteins and Signalling Domains for Antibiotic Discovery

Cholesterol Biases the Conformational Landscape of the Chemokine Receptor CCR3: A MAS SSNMR-Filtered Molecular Dynamics Study

Quantitative study of unsaturated transport of glycerol through aquaglyceroporin that has high affinity for glycerol

Contact Info

Product

Resources

About